1,404 results on '"Androstenes"'
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2. VIRIDIN. II. OXIDATION BY CHROMIC ACID.
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MCCLOSKEY P
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- Androstenes, Antifungal Agents, Bacteriocins, Chemical Phenomena, Chemistry, Chromates, Oxidation-Reduction, Research
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- 1965
- Full Text
- View/download PDF
3. STEROIDS. CLXXXIV. 2-FORMYL-2-ANDROSTENES AND RELATED COMPOUNDS. A NEW CLASS OF POTENT ANABOLIC AGENTS.
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ORR JC, HALPERN O, and BOWERS A
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- Anabolic Agents, Androstenes, Chemical Phenomena, Chemistry, Research, Steroids, Testosterone Congeners
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- 1962
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- View/download PDF
4. VIRIDIN. I. ISOLATION AND CHARACTERISATION.
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GROVE JF, MOFFATT JS, and VISCHER EB
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- Androstenes, Antifungal Agents, Bacteriocins, Chemical Phenomena, Chemistry, Research
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- 1965
- Full Text
- View/download PDF
5. Quality of Life in Men With Prostate Cancer Randomly Allocated to Receive Docetaxel or Abiraterone in the STAMPEDE Trial
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Ruth E Langley, David P. Dearnaley, H. Rush, Silke Gillessen, Mahesh K. B. Parmar, Andrew Protheroe, Robin Millman, Shaun Tolan, Zaf Malik, Peter Hoskin, Christopher D. Brawley, Duncan C. Gilbert, Simon Chowdhury, Noel W. Clarke, Sarah Rudman, Nicholas D. James, Carla Perna, Neil McPhail, J. Martin Russell, Robert Jones, John Wagstaff, Adrian Cook, Gerhardt Attard, Joanna Gale, Salil Vengalil, Emma Gray, Alison Birtle, David Gareth Fackrell, Jacob Tanguay, Matthew R. Sydes, Archie Macnair, Joe M. O'Sullivan, Chris Parker, Alicia K. Morgans, Laura Murphy, David Matheson, and C. Pugh
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Male ,Oncology ,Cancer Research ,medicine.medical_specialty ,Abiraterone Acetate ,Docetaxel ,Article ,Androgen deprivation therapy ,chemistry.chemical_compound ,Prostate cancer ,Quality of life ,Prednisone ,Internal medicine ,Antineoplastic Combined Chemotherapy Protocols ,otorhinolaryngologic diseases ,Humans ,Medicine ,business.industry ,Abiraterone acetate ,Prostatic Neoplasms ,Androgen Antagonists ,medicine.disease ,Abiraterone ,chemistry ,Quality of Life ,Prednisolone ,Androstenes ,business ,medicine.drug - Abstract
PURPOSE Docetaxel and abiraterone acetate plus prednisone or prednisolone (AAP) both improve survival when commenced alongside standard of care (SOC) androgen deprivation therapy in locally advanced or metastatic hormone-sensitive prostate cancer. Thus, patient-reported quality of life (QOL) data may guide treatment choices. METHODS A group of patients within the STAMPEDE trial were contemporaneously enrolled with the possibility of being randomly allocated to receive either docetaxel + SOC or AAP + SOC. A mixed-model assessed QOL in those who had completed at least one QLQ-C30 + PR25 questionnaire. The primary outcome measure was difference in global-QOL (QLQ-C30 Q29&30) between patients allocated to docetaxel + SOC or AAP + SOC over the 2 years after random assignment, with a predefined criterion for clinically meaningful difference of > 4.0 points. Secondary outcome measures included longitudinal comparison of functional domains, pain, and fatigue, plus global-QOL at defined timepoints. RESULTS Five hundred fifteen patients (173 docetaxel + SOC and 342 AAP + SOC) were included. Baseline characteristics, proportion of missing data, and mean baseline global-QOL scores (docetaxel + SOC 77.8 and AAP + SOC 78.0) were similar. Over the 2 years following random assignment, the mean modeled global-QOL score was +3.9 points (95% CI, +0.5 to +7.2; P = .022) higher in patients allocated to AAP + SOC. Global-QOL was higher for patients allocated to AAP + SOC over the first year (+5.7 points, 95% CI, +3.0 to +8.5; P < .001), particularly at 12 (+7.0 points, 95% CI, +3.0 to +11.0; P = .001) and 24 weeks (+8.3 points, 95% CI, +4.0 to +12.6; P < .001). CONCLUSION Patient-reported QOL was superior for patients allocated to receive AAP + SOC, compared with docetaxel + SOC over a 2-year period, narrowly missing the predefined value for clinical significance. Patients receiving AAP + SOC reported clinically meaningful higher global-QOL scores throughout the first year following random assignment.
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- 2022
6. Characterizing Out-of-Pocket Payments and Financial Assistance for Patients Prescribed Abiraterone and Enzalutamide at an Academic Cancer Center Specialty Pharmacy
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Angelina Y Jeong, Mary K. Oerline, Megan E.V. Caram, Rachel L McDevitt, Christine M. Veenstra, Andrea Roman, Eric B Schwartz, and Elyssa Henry
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Male ,media_common.quotation_subject ,MEDLINE ,Pharmacy ,ORIGINAL CONTRIBUTIONS ,chemistry.chemical_compound ,Neoplasms ,Nitriles ,Phenylthiohydantoin ,Humans ,Medicine ,Enzalutamide ,Center (algebra and category theory) ,health care economics and organizations ,media_common ,Finance ,Oncology (nursing) ,business.industry ,Health Policy ,Cancer ,medicine.disease ,Payment ,Abiraterone ,Oncology ,chemistry ,Specialty pharmacy ,Benzamides ,Androstenes ,Health Expenditures ,business - Abstract
PURPOSE: Abiraterone and enzalutamide are commonly used oral cancer therapies for patients with prostate cancer, both with potentially high out-of-pocket costs for patients. We investigated the prevalence of financial assistance mechanisms used to alleviate out-of-pocket costs and the association of these mechanisms with timing of treatment initiation of abiraterone or enzalutamide. METHODS: Using data from the medical center's specialty pharmacy, we identified first prescriptions for abiraterone or enzalutamide between January 1, 2017, and March 31, 2019. Prescriptions dispensed at an external pharmacy or that were discontinued for reasons unrelated to cost were excluded. Patient demographics, insurance coverage, out-of-pocket cost, and number of days between prescribed date and pill-to-mouth date were collected. RESULTS: Among 220 prescriptions in our final cohort, 185 were filled through our internal specialty pharmacy, 23 through a manufacturer-sponsored patient assistance program (PAP), and 12 were never filled because of cost. One third of the prescriptions in our final cohort (n = 66) were filled with financial assistance: PAP (10%), copay cards (9%), and grants (11%). The median amount of assistance received for the first fill was $2,860 US dollars (USD) (interquartile range $1,856-$10,717 USD). Prescriptions with an out-of-pocket cost < $100 USD were filled in the shortest time (median 5 days), whereas those filled through a PAP had the longest time to initiation (median 30.5 days). CONCLUSION: Among patients prescribed oral therapies for prostate cancer at a single institution, one third of patients received financial assistance. Although receiving assistance is likely to improve financial toxicity, waiting for assistance may lead to longer time to initiation of medication.
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- 2022
7. Beyond Frontline Therapy with Abiraterone and Enzalutamide in Metastatic Castration-Resistant Prostate Cancer: A Real-World US Study
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Neal D. Shore, Louise Yu, Dominique Lejeune, S. Ghate, François Laliberté, Jeri Kim, Lingfeng Yang, Mei Sheng Duh, Malena Mahendran, and Raluca Ionescu-Ittu
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Adult ,Male ,Oncology ,medicine.medical_specialty ,Urology ,Population ,Abiraterone Acetate ,chemistry.chemical_compound ,Prostate cancer ,Internal medicine ,Antineoplastic Combined Chemotherapy Protocols ,Nitriles ,Phenylthiohydantoin ,medicine ,Overall survival ,Humans ,Enzalutamide ,education ,Aged ,Retrospective Studies ,education.field_of_study ,business.industry ,medicine.disease ,Prostatic Neoplasms, Castration-Resistant ,Abiraterone ,Treatment Outcome ,Docetaxel ,chemistry ,Benzamides ,Cohort ,Adenocarcinoma ,Androstenes ,business ,medicine.drug - Abstract
Background Real-world evidence suggest that next generation hormonal agents (NHAs) abiraterone and enzalutamide were preferred as first-line (1L) therapies for metastatic castration-resistant prostate cancer (mCRPC) in the United States (US) pre-2020, with chemotherapies, particularly docetaxel, being preferred in subsequent lines (2L+). This real-world study described patient characteristics, treatment patterns, time on treatment (ToT) and overall survival (OS) among patients with mCRPC treated with 2L and 3L docetaxel post-NHAs in the mCRPC setting. Methods Adults with confirmed adenocarcinoma mCRPC diagnosis and ≥1 month of follow-up post-diagnosis were selected from a US electronic health record-derived oncology de-identified database (01/2013–03/2019). Based on the observed line of therapy sequences post-mCRPC diagnosis, patients who received NHA therapy in 1L and docetaxel therapy in 2L were included in the 2L docetaxel cohort, and patients who received NHA therapy in both 1L and 2L and docetaxel therapy in 3L were included in the 3L docetaxel cohort. ToT and OS were evaluated using Kaplan-Meier analysis. Results Among 5,213 patients with mCRPC, 278 and 166 were included in the 2L and the 3L docetaxel cohorts, respectively (median age: 73 years for both cohorts). ADT was the most used class of medication pre-mCRPC (>75%). For the 2L cohort, the most common sequence post-mCRPC was 1L abiraterone → 2L docetaxel (52.5%), while the median ToT and OS post-2L start were 4.1 and 10.5 months, respectively; for the 3L cohort, the most common sequence post-mCRPC was 1L abiraterone → 2L enzalutamide → 3L docetaxel (67.5%), while the median ToT and OS post-3L start were 3.8 and 8.7 months, respectively. Conclusions This real-world study provides novel data on patients treated with docetaxel post-NHAs in a mCRPC setting and highlights the critical unmet need for developing more effective treatment options in this population.
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- 2021
8. Comparison of out-of-pocket costs and adherence between the two arms of the prospective, randomized abiraterone food effect trial
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Alvin Wong, Daniel M. Geynisman, Brian L. Heiss, Elia Martinez, Wei Peng Yong, Walter M. Stadler, and Russell Z. Szmulewitz
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Male ,medicine.medical_specialty ,Article ,law.invention ,chemistry.chemical_compound ,Prostate cancer ,Randomized controlled trial ,law ,Internal medicine ,medicine ,Humans ,Prospective Studies ,Trial registration ,FOOD EFFECT ,Meal ,business.industry ,Abiraterone acetate ,medicine.disease ,Prostatic Neoplasms, Castration-Resistant ,Abiraterone ,Oncology ,chemistry ,Androstenes ,Health Expenditures ,business ,Enhanced absorption - Abstract
Purpose Abiraterone acetate, prescribed for metastatic prostate cancer, has enhanced absorption with food. This effect was exploited in a randomized trial which showed noninferiority of PSA decline for 250 mg abiraterone with a low-fat meal (LOW) compared to 1,000 mg abiraterone fasting (STD). Drug was obtained via patient insurance. Patient out-of-pocket costs and adherence were surveyed. Methods Trial participants were randomized to STD or LOW, and surveys of adherence and out-of-pocket costs were administered at baseline and just before coming off study (follow-up). Results Out-of-pocket costs were available from 20 of 36 STD and 21 of 36 LOW patients. Median out-of-pocket costs for a month of drug were $0 (LOW) and $5 (STD); mean costs were $43.61 (LOW) and $393.83 (STD). The two groups did not differ significantly (p = 0.421). Maximum out-of-pocket cost was $1,000 (LOW) and $4,000 (STD). Monthly out-of-pocket costs > $500 were found in 1 LOW and 5 STD patients. For adherence, only 11 STD and 19 LOW patients had questionnaires completed at both baseline and follow-up. STD adherence was 98.18% at baseline and 91.69% at follow-up, differing significantly (p = 0.0078). LOW adherence was 96.52% at baseline and 97.86% at follow-up, not differing significantly (p = 0.3511). Adherence did not correlate with demographics. At follow-up, increasing adherence correlated significantly with decreasing dose (p = 0.013; rho = - 0.458). Conclusions Out-of-pocket costs did not differ significantly in this limited analysis. Adherence was significantly different in STD as the trial progressed, which was not found in LOW. Trial registration ClinicalTrials.gov NCT01543776; registered March 5, 2012.
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- 2021
9. Loss of SNAI2 in Prostate Cancer Correlates With Clinical Response to Androgen Deprivation Therapy
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Stefano Mangiola, Jeremy Grummet, Michael Kerger, Paul Ruljancich, Ryan Stuchbery, David Clarke, Justin S. Peters, Andrew Ryan, Niall M. Corcoran, Phillip Parente, Nicholas Howard, Christopher M. Hovens, Natalie Kurganovs, Sam Norden, Anthony J. Costello, Anne Ngyuen, Corrina A Grima, Patrick McCoy, Geoff Macintyre, Philip Dundee, Marek Cmero, and Ken Chow
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Male ,0301 basic medicine ,Cancer Research ,Epithelial-Mesenchymal Transition ,Antineoplastic Agents, Hormonal ,Bicalutamide ,Regulator ,Tosyl Compounds ,Androgen deprivation therapy ,03 medical and health sciences ,chemistry.chemical_compound ,Prostate cancer ,0302 clinical medicine ,Downregulation and upregulation ,Nitriles ,Humans ,Medicine ,Anilides ,Degarelix ,Aged ,business.industry ,Hormonal Therapy ,Androgen Antagonists ,ORIGINAL REPORTS ,medicine.disease ,Gene Expression Regulation, Neoplastic ,Androgen receptor ,Prostatic Neoplasms, Castration-Resistant ,030104 developmental biology ,Oncology ,chemistry ,Drug Resistance, Neoplasm ,030220 oncology & carcinogenesis ,Cancer research ,Androstenes ,Snail Family Transcription Factors ,business ,Oligopeptides ,Reprogramming ,Signal Transduction ,medicine.drug - Abstract
PURPOSE Androgen receptor (AR) signaling is important in prostate cancer progression, and therapies that target this pathway have been the mainstay of treatment for advanced disease for over 70 years. Tumors eventually progress despite castration through a number of well-characterized mechanisms; however, little is known about what determines the magnitude of response to short-term pathway inhibition. METHODS We evaluated a novel combination of AR-targeting therapies (degarelix, abiraterone, and bicalutamide) and noted that the objective patient response to therapy was highly variable. To investigate what was driving treatment resistance in poorly responding patients, as a secondary outcome we comprehensively characterized pre- and post-treatment samples using both whole-genome and RNA sequencing. RESULTS We find that resistance following short-term treatment differs molecularly from typical progressive castration-resistant disease, associated with transcriptional reprogramming, to a transitional epithelial-to-mesenchymal transition (EMT) phenotype rather than an upregulation of AR signaling. Unexpectedly, tolerance to therapy appears to be the default state, with treatment response correlating with the prevalence of tumor cells deficient for SNAI2, a key regulator of EMT reprogramming. CONCLUSION We show that EMT characterizes acutely resistant prostate tumors and that deletion of SNAI2, a key transcriptional regulator of EMT, correlates with clinical response.
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- 2021
10. Real-world incidence of symptomatic skeletal events and bone-modifying agent use in castration-resistant prostate cancer – an Australian multi-centre observational study
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Marie C Semira, Francis Parnis, Angelyn Anton, Peter Gibbs, Arun Azad, Javier Torres, Lavinia Spain, Ashray Gunjur, Andrew Weickhardt, Phillip Parente, Jeffrey C. Goh, Edmond M. Kwan, Shirley Wong, Ben Tran, Carmel Pezaro, and J. Shapiro
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Adult ,Male ,Cancer Research ,medicine.medical_specialty ,Antineoplastic Agents ,Bone Neoplasms ,Docetaxel ,Zoledronic Acid ,chemistry.chemical_compound ,Prostate cancer ,Internal medicine ,Nitriles ,Phenylthiohydantoin ,medicine ,Humans ,Enzalutamide ,Adverse effect ,Aged ,Retrospective Studies ,Aged, 80 and over ,Bone Density Conservation Agents ,business.industry ,Incidence ,Australia ,Retrospective cohort study ,Middle Aged ,medicine.disease ,Prostatic Neoplasms, Castration-Resistant ,Treatment Outcome ,Denosumab ,Zoledronic acid ,Oncology ,chemistry ,Benzamides ,Cohort ,Androstenes ,business ,Spinal Cord Compression ,medicine.drug - Abstract
INTRODUCTION: Bone metastases occur frequently in castration-resistant prostate cancer (CRPC) and may lead to skeletal-related events (SREs), including symptomatic skeletal events (SSEs). Bone-modifying agents (BMAs) delay SREs and SSEs. However, the real-world use of BMAs is debated given the absence of demonstrated survival advantage and potential adverse events (AEs). Our retrospective study examined BMA use and SSE rates in Australian patients with CRPC. METHODS: Patients with CRPC and bone metastases were identified from the electronic CRPC Australian Database. Patient characteristics, treatment patterns and AEs were analysed. Descriptive statistics reported baseline characteristics, SSE rates and BMA use. Comparisons between groups used t-tests and Chi-square analyses. Overall survival was calculated by the Kaplan-Meier method. RESULTS: A total of 532 eligible patients were identified with a median age of 73 years (range: 44-97 years). BMAs were prescribed in 232 men (46%), 183 of whom received denosumab. Patients receiving first-line docetaxel for CRPC were more likely to commence BMAs than those receiving abiraterone or enzalutamide (51% vs 31% vs 38%; p = 0.004). SSEs occurred in 148 men (28%), most commonly symptomatic lesions requiring intervention (75%). At the time of initial SSEs, only 28% were receiving BMAs. Patients treated at sites with lower BMA use (
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- 2021
11. Biotransformation of Current-Use Progestin Dienogest and Drospirenone in Laboratory-Scale Activated Sludge Systems Forms High-Yield Products with Altered Endocrine Activity
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Kelly E. Kim, Zhenyu Tian, Edward P. Kolodziej, Haoqi Nina Zhao, Rui Wang, and Kenji Lam
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medicine.drug_class ,Hydroxylation ,chemistry.chemical_compound ,Biotransformation ,Pregnancy ,medicine ,Humans ,Nandrolone ,Environmental Chemistry ,Organic chemistry ,Spirorenone ,chemistry.chemical_classification ,Sewage ,fungi ,Drospirenone ,General Chemistry ,Activated sludge ,chemistry ,Dienogest ,Androstenes ,Female ,Progestins ,Laboratories ,Progestin ,Lactone ,medicine.drug - Abstract
Dienogest (DIE) and drospirenone (DRO) are two fourth-generation synthetic progestins widely used as oral contraceptives. Despite their increasing detection in wastewaters and surface waters, their fate during biological wastewater treatment is unclear. Here, we investigated DIE and DRO biotransformation with representative activated sludge batch incubations and identified relevant transformation products (TPs) using high-resolution mass spectrometry. DIE exhibited slow biotransformation (16-30 h half-life) and proceeded through a quantitative aromatic dehydrogenation to form TP 309 (molar yields of ∼55%), an aromatic TP ∼30% estrogenic as 17β-estradiol. DRO experienced more rapid biotransformation (
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- 2021
12. Efficacy of systemic therapies in men with metastatic castration resistant prostate cancer harboring germline ATM versus BRCA2 mutations
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Elena Castro, Rebeca Lozano, Petros Grivas, Vadim Sokolov, Navonil De Sarkar, Bruce Montgomery, David Olmos, Celestia S. Higano, Alexandra O. Sokolova, Peter S. Nelson, Michael T. Schweizer, Catherine Handy Marshall, Emmanuel S. Antonarakis, Roman Gulati, Evan Y. Yu, Channing J. Paller, Todd Yezefski, Oliver Sartor, Heather H. Cheng, and Elisa Ledet
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Male ,Oncology ,medicine.medical_specialty ,Medication Therapy Management ,Urology ,Antineoplastic Agents ,Ataxia Telangiectasia Mutated Proteins ,Docetaxel ,Poly(ADP-ribose) Polymerase Inhibitors ,medicine.disease_cause ,Article ,Germline ,Prostate cancer ,chemistry.chemical_compound ,Germline mutation ,Internal medicine ,Nitriles ,Phenylthiohydantoin ,medicine ,Humans ,Enzalutamide ,Stage (cooking) ,Germ-Line Mutation ,Neoplasm Staging ,Retrospective Studies ,BRCA2 Protein ,Mutation ,business.industry ,Patient Selection ,Middle Aged ,Prostate-Specific Antigen ,medicine.disease ,Survival Analysis ,Prostatic Neoplasms, Castration-Resistant ,Exact test ,chemistry ,Benzamides ,Androstenes ,Neoplasm Grading ,business ,medicine.drug - Abstract
BACKGROUND Among men with metastatic prostate cancer, about 10% have germline alterations in DNA damage response genes. Most studies have examined BRCA2 alone or an aggregate of BRCA1/2 and ATM. Emerging data suggest that ATM mutations may have distinct biology and warrant individual evaluation. The objective of this study is to determine whether response to prostate cancer systemic therapies differs between men with germline mutations in ATM (gATM) and BRCA2 (gBRCA2). METHODS This is an international multicenter retrospective matched cohort study of men with prostate cancer harboring gATM or gBRCA2. PSA50 response (≥50% decline in prostate-specific antigen) was compared using Fisher's exact test. RESULTS AND LIMITATIONS The study included 45 gATM and 45 gBRCA2 patients, matched on stage and year of germline testing. Patients with gATM and gBRCA2 had similar age, Gleason grade, and PSA at diagnosis. We did not observe differences in PSA50 responses to abiraterone, enzalutamide, or docetaxel in metastatic castration resistant prostate cancer between the two groups; however, 0/7 with gATM and 12/14 with gBRCA2 achieved PSA50 response to PARPi (p
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- 2021
13. Estetrol-drospirenone combination oral contraceptive: North American phase 3 efficacy and safety results
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Sharon L. Achilles, Andrew M. Kaunitz, Carolyn Westhoff, David F. Archer, Jeffrey T. Jensen, Céline Bouchard, Mitchell D. Creinin, Melissa J. Chen, and Jean-Michel Foidart
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Reproductive health and childbirth ,Ethinyl Estradiol ,chemistry.chemical_compound ,0302 clinical medicine ,Pregnancy ,030212 general & internal medicine ,030219 obstetrics & reproductive medicine ,Combined ,Obstetrics ,Estetrol ,Obstetrics and Gynecology ,Metrorrhagia ,Contraceptives ,Hematology ,Contraceptives, Oral, Combined ,6.1 Pharmaceuticals ,Pill ,Public Health and Health Services ,Androstenes ,Female ,Patient Safety ,medicine.symptom ,medicine.drug ,Oral ,medicine.medical_specialty ,Clinical Trials and Supportive Activities ,Clinical Sciences ,Oral contraceptive ,Paediatrics and Reproductive Medicine ,03 medical and health sciences ,Drospirenone ,Clinical Research ,medicine ,Humans ,Vaginal bleeding ,Obstetrics & Reproductive Medicine ,business.industry ,Prevention ,Contraception/Reproduction ,Evaluation of treatments and therapeutic interventions ,Estrogens ,medicine.disease ,Regimen ,Reproductive Medicine ,chemistry ,North America ,Pearl index ,business ,Pearl Index - Abstract
Objective To assess efficacy, cycle control, and safety of an oral contraceptive containing estetrol (E4) 15 mg and drospirenone (DRSP) 3 mg. Study design Women aged 16 to 50 years with a body mass index ≤35 kg/m2 enrolled in this multicenter, open-label, 13-cycle, phase 3 trial evaluating E4/DRSP in a 24-active/4-placebo regimen. Follow-up was scheduled at Cycles 2, 4, 7, and 10 and within 3 weeks of completing Cycle 13. Participants used daily diaries to record pill use and vaginal bleeding. We evaluated efficacy outcomes in women 16 to 35 years and bleeding patterns and safety (adverse events [AEs]) in all participants. We assessed overall and method-failure pregnancy rates using the Pearl index (PI) and life-table analysis. Scheduled bleeding included spotting or bleeding starting during the 4-day placebo period or first 3 days of the next cycle. Results We enrolled 1864 women of whom 1674 were 16 to 35 years. Women 16 to 35 years had a PI of 2.65 (95% CI 1.73–3.88), method-failure PI of 1.43 (95% CI 0.7–2.39) and 13-cycle life-table pregnancy rate of 2.1%. Scheduled bleeding occurred in 82.9% to 87.0% of women per cycle; median duration was 4.5 days. Unscheduled bleeding decreased from 30.3% in Cycle 1 to 21.3% to 22.1% during Cycles 2 to 4 and remained stable (15.5% to 19.2%) thereafter. The most frequently reported AEs were headache (5.0%) and metrorrhagia (4.6%). One-hundred thirty-two (7.1%) women discontinued the study early for an AE, most commonly for metrorrhagia (0.9%) and menorrhagia (0.8%). No thromboembolic events occurred. Conclusion E4/DRSP is an effective oral contraceptive with a predictable bleeding pattern for most women and low AE rates. Implications statement A new oral contraceptive with a novel estrogen, estetrol, combined with drospirenone has efficacy and safety within the range of other available oral contraceptives. Large phase 4 studies will be needed to confirm if this combination is associated with an improved adverse event profile or lower thrombosis risk.
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- 2021
14. Circulating and Intratumoral Adrenal Androgens Correlate with Response to Abiraterone in Men with Castration-Resistant Prostate Cancer
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Alvin M. Matsumoto, Nima Sharifi, Michael T. Schweizer, Heather H. Cheng, R. Bruce Montgomery, Mary-Ellen Taplin, P.W. Kantoff, Felix S. Chew, Evan Y. Yu, Orpheus Kolokythas, Steven P. Balk, Peter S. Nelson, Brett T. Marck, and Elahe A. Mostaghel
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Adult ,Male ,Oncology ,Cancer Research ,medicine.medical_specialty ,Antineoplastic Agents, Hormonal ,medicine.drug_class ,Phases of clinical research ,Article ,chemistry.chemical_compound ,Prostate cancer ,Prednisone ,Internal medicine ,Humans ,Medicine ,Neoplasm Metastasis ,Correlation of Data ,Testosterone ,Aged ,Aged, 80 and over ,Tumor microenvironment ,business.industry ,Abiraterone acetate ,Middle Aged ,medicine.disease ,Androgen ,Androgen receptor ,Drug Combinations ,Prostatic Neoplasms, Castration-Resistant ,Treatment Outcome ,chemistry ,Adrenal Cortex ,Androgens ,Androstenes ,business ,medicine.drug - Abstract
Purpose: In metastatic castration-resistant prostate cancer (mCRPC) low serum androgens prior to starting abiraterone acetate (AA) is associated with more rapid progression. We evaluated the effect of AA on androgens in castration-resistant prostate cancer (CRPC) metastases and associations of intratumoral androgens with response. Experimental Design: We performed a phase II study of AA plus prednisone in mCRPC. The primary outcome was tissue testosterone at 4 weeks. Exploratory outcomes were association of steroid levels and genomic alterations with response, and escalating AA to 2,000 mg at progression. Results: Twenty-nine of 30 men were evaluable. Testosterone in metastatic biopsies became undetectable at 4 weeks (P < 0.001). Serum and tissue dehydroepiandrosterone sulfate (DHEAS) remained detectable in many patients and was not increased at progression. Serum and tissue DHEAS in the lowest quartile (pretreatment), serum DHEAS in the lowest quartile (4 weeks), and undetectable tissue DHEAS (on-therapy) associated with rapid progression (20 vs. 48 weeks, P = 0.0018; 20 vs. 52 weeks, P = 0.0003; 14 vs. 40 weeks, P = 0.0001; 20 vs. 56 weeks, P = 0.02, respectively). One of 16 men escalating to 2,000 mg had a 30% PSA decline; 13 developed radiographic progression by 12 weeks. Among patients with high serum DHEAS at baseline, wild-type (WT) PTEN status associated with longer response (61 vs. 33 weeks, P = 0.02). Conclusions: Low-circulating adrenal androgen levels are strongly associated with an androgen-poor tumor microenvironment and with poor response to AA. Patients with CRPC with higher serum DHEAS levels may benefit from dual androgen receptor (AR)-pathway inhibition, while those in the lowest quartile may require combinations with non–AR-directed therapy.
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- 2021
15. The effect of drug loading on the properties of abiraterone–hydroxypropyl beta cyclodextrin solid dispersions processed by solvent free KinetiSol® technology
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Angela Spangenberg, Yongchao Su, Urvi Gala, Robert O. Williams, and Dave A. Miller
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Drug ,Recrystallization (geology) ,Chemistry, Pharmaceutical ,Drug Compounding ,media_common.quotation_subject ,Biological Availability ,Pharmaceutical Science ,02 engineering and technology ,030226 pharmacology & pharmacy ,Excipients ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Differential scanning calorimetry ,Pharmacokinetics ,In vivo ,Dissolution ,media_common ,Abiraterone acetate ,General Medicine ,021001 nanoscience & nanotechnology ,2-Hydroxypropyl-beta-cyclodextrin ,Bioavailability ,Drug Liberation ,chemistry ,Androstenes ,0210 nano-technology ,Biotechnology ,Nuclear chemistry - Abstract
Abiraterone is a poorly water-soluble drug used in the treatment of prostate cancer. In our previous study, we reported that KinetiSol® processed solid dispersions (KSDs) based on hydroxypropyl β-cyclodextrin (HPBCD) showed improved dissolution and pharmacokinetics of abiraterone. However, the nature of abiraterone-HPBCD interaction within the KSDs or the effect of drug loading on the physicochemical properties and in vivo performance of HPBCD-based KSDs remain largely unknown. We hypothesize that KinetiSol technology can prepare abiraterone-HPBCD complexes within KSDs and that increasing the drug loading beyond an optimal point reduces the in vitro and in vivo performance of these KSDs. To confirm our hypothesis, we developed KSDs with 10-50% w/w drug loading and analyzed them using X-ray diffractometry and modulated differential scanning calorimetry. We found that KSDs containing 10-30% drug were amorphous. Interestingly, two-dimensional solid-state nuclear magnetic resonance and Raman spectroscopy indicated that the abiraterone-HPBCD complexes were formed. At elevated temperatures, the 10% and 20% drug-loaded KSDs were physically stable, while the 30% drug-loaded KSD showed recrystallization of abiraterone. In vitro dissolution and in vivo pharmacokinetic performances improved as the drug loading decreased; we attribute this to increased noncovalent interactions between abiraterone and HPBCD at lower drug loadings. Overall, the 10% drug loaded KSD showed a dissolution enhancement of 15.7-fold compared to crystalline abiraterone, and bioavailability enhancement of 3.9-fold compared to the commercial abiraterone acetate tablet Zytiga®. This study is first to confirm that KinetiSol, a high-energy, solvent-free technology, is capable of forming abiraterone-HPBCD complexes. Furthermore, in terms of in vitro and in vivo performance, a 10% drug load is optimal.
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- 2021
16. Treatment and Patient Selection for Patients with Metastatic Castration-resistant Prostate After Progression on Docetaxel and Abiraterone/Enzalutamide: When to Play Your CARD and When to Do Your PARP
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Jason P. Izard, Andrew G. Robinson, and Francisco E. Vera-Badillo
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Male ,Oncology ,medicine.medical_specialty ,Urology ,medicine.medical_treatment ,030232 urology & nephrology ,Docetaxel ,Poly(ADP-ribose) Polymerase Inhibitors ,03 medical and health sciences ,Prostate cancer ,chemistry.chemical_compound ,0302 clinical medicine ,Prostate ,Internal medicine ,Nitriles ,Phenylthiohydantoin ,medicine ,Humans ,Enzalutamide ,neoplasms ,Chemotherapy ,business.industry ,Patient Selection ,medicine.disease ,Androgen receptor ,Prostatic Neoplasms, Castration-Resistant ,medicine.anatomical_structure ,Pharmaceutical Preparations ,chemistry ,Cabazitaxel ,030220 oncology & carcinogenesis ,Benzamides ,PARP inhibitor ,Androstenes ,business ,Orchiectomy ,medicine.drug - Abstract
For patients with metastatic castration-resistant prostate cancer (mCRPC) progressing after an androgen receptor axis-targeted therapy and docetaxel, poly (ADP-ribose) polymerase (PARP) inhibitors and chemotherapy with cabazitaxel have shown promise. We address the trials for the two approaches and consider possible sequencing of these drugs. We suggest that only patients with a BRCA2 mutation should receive a PARP inhibitor, and docetaxel or cabazitaxel should be favored in the absence of BRCA2 alterations, provided the patient is naïve to these drugs.
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- 2021
17. Exosomal TUBB3 mRNA expression of metastatic castration‐resistant prostate cancer patients: Association with patient outcome under abiraterone
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Guangxi Sun, Jindong Dai, Sha Zhu, Haoran Zhang, Jiayu Liang, Hao Zeng, Xudong Zhu, Yuchao Ni, Zilin Wang, Pengfei Shen, Yaowen Zhang, Xingming Zhang, Zhenhua Liu, Jinge Zhao, and Junru Chen
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Male ,Oncology ,Cancer Research ,medicine.medical_specialty ,Mrna expression ,exosomes ,Castration resistant ,Risk Assessment ,prostatic neoplasms ,Prostate cancer ,chemistry.chemical_compound ,Tubulin ,Internal medicine ,Biomarkers, Tumor ,medicine ,Clinical endpoint ,Humans ,Radiology, Nuclear Medicine and imaging ,Prospective Studies ,RNA, Messenger ,TUBB3 ,RC254-282 ,Research Articles ,Aged ,ECOG Score ,business.industry ,Abiraterone acetate ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,Clinical Cancer Research ,Prostate-Specific Antigen ,medicine.disease ,Progression-Free Survival ,messenger ,Gene Expression Regulation, Neoplastic ,Prostatic Neoplasms, Castration-Resistant ,Abiraterone ,abiraterone acetate ,chemistry ,Drug Resistance, Neoplasm ,RNA ,Androstenes ,Kallikreins ,business ,Research Article - Abstract
Background To use ddPCR to quantify plasma exosomal class III β‐tubulin (βIII‐tubulin, TUBB3, encoded by the TUBB3 gene) mRNA expression in metastatic castration‐resistant prostate cancer (mCRPC) patients, and study the association of this expression with abiraterone efficacy. Methods Blood samples were prospectively collected from 52 mCRPC patients using abiraterone as first‐line therapy to measure plasma exosomal TUBB3 mRNA expression value before the initiation of abiraterone. Study endpoints were PSA response rate, PSA‐progression‐free survival (PSA‐PFS), and overall survival (OS, from CRPC to death). Results Patients with positive exosomal TUBB3 expression showed shorter PSA‐PFS (negative TUBB3 vs. positive TUBB3: 11.0 vs. 7.9 months; p = 0.014). Further analysis demonstrated that patients with strongly positive exosomal TUBB3 (>20 copies/20 µl) was associated with even shorter PSA‐PFS (negative TUBB3 vs. positive TUBB3 [20 copies/20 µl]: 11.0 vs. 8.3 vs. 3.6 months, p = 0.005). In multivariate analyzes, TUBB3 (+) (HR: 2.114, p = 0.033) and ECOG score >2 (HR: 3.039, p = 0.006) were independent prognosticators of poor PSA‐PFS. PSA response and OS did not present significant differences. Conclusion The exosomal TUBB3 mRNA expression level is associated with poor PSA‐PFS of abiraterone in mCRPC patients. The detection of exosomal TUBB3 can be valuable in their management., In this study, we presented this novel, non‐invasive biomarker for abiraterone resistance in mCRPC patients using a ddPCR approach to quantificationally measure the exosomal TUBB3 mRNA expression. We found that a higher TUBB3 level is correlated with shorter progression time after first‐line abiraterone treatment in mCRPC patients.
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- 2021
18. Effectiveness of first-line abiraterone versus enzalutamide among patients ≥80 years of age with metastatic castration-resistant prostate cancer: A retrospective propensity score–weighted comparative cohort study
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Daniel Khalaf, Maryam Soleimani, Werner Struss, Daygen Finch, Katherine Sunderland, Joanna Vergidis, Kevin Zou, Christian Kollmannsberger, Krista Noonan, B.J. Eigl, Muhammad Zulfiqar, Kim N. Chi, and Lucia Nappi
- Subjects
Male ,0301 basic medicine ,Oncology ,Cancer Research ,medicine.medical_specialty ,Time Factors ,Population ,03 medical and health sciences ,Prostate cancer ,chemistry.chemical_compound ,0302 clinical medicine ,Internal medicine ,Nitriles ,Phenylthiohydantoin ,medicine ,Humans ,Enzalutamide ,Propensity Score ,education ,Retrospective Studies ,Aged, 80 and over ,education.field_of_study ,Dose-Response Relationship, Drug ,Proportional hazards model ,business.industry ,Age Factors ,Abiraterone acetate ,Prostate-Specific Antigen ,medicine.disease ,Progression-Free Survival ,Discontinuation ,Prostatic Neoplasms, Castration-Resistant ,030104 developmental biology ,chemistry ,Tolerability ,030220 oncology & carcinogenesis ,Benzamides ,Propensity score matching ,Androstenes ,Kallikreins ,business - Abstract
Metastatic castration-resistant prostate cancer (mCRPC) disproportionately affects the elderly. There is limited data assessing the efficacy and tolerability of abiraterone acetate (AA) versus enzalutamide in this population.To compare the clinical efficacy and tolerability of AA versus enzalutamide in patients ≥ 80 years with mCRPC.A retrospective propensity-weighted comparative cohort study of first-line AA versus enzalutamide among patients with mCRPC aged ≥80 years.Inverse probability treatment weights based on propensity scores were generated to assess the treatment effect of AA versus enzalutamide on time to PSA progression (TTPP), time to progression (TTP) (first of PSA/radiographic/clinical progression) and overall survival using a weighted Cox proportional hazards model. PSA response rate (PSA RR) was compared between groups using ΧOne hundred fifty-three patients received AA, and 125 received enzalutamide. Enzalutamide was associated with higher PSA RR (61.6% vs 43.8%, P 0.004), and TTP (hazard ratio [HR] 0.66, 95% confidence interval [CI] 0.50-0.88, P = 0.01) but not TTPP (HR 0.73, 95% CI 0.53-1.01, P = 0.06). There were significantly more dose reductions with enzalutamide (22.9% vs 44.8%, P 0.001) but there was no interaction between median proportion of full dose received and TTPP or TTP for either drug. Rates of treatment discontinuation (for reasons other than progression) were also significantly different between AA and enzalutamide (28.8% vs 40.8%, respectively, P = 0.04). The most common reason for dose reductions and discontinuation of enzalutamide was fatigue (30.4% and 5.6%, respectively).Despite more dose reductions and a higher treatment discontinuation rate, enzalutamide was associated with a higher PSA RR and longer time to progression, than AA. Given that clinical outcomes were not adversely impacted by decreased treatment exposure, dose modification may be a useful treatment strategy to balance toxicity and tolerance.
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- 2021
19. Evolution of Castration-Resistant Prostate Cancer in ctDNA during Sequential Androgen Receptor Pathway Inhibition
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Conrad D. Oja, Amanda Wong, Simon Yuen Fai Fu, Bernhard J. Eigl, Sinja Taavitsainen, Joonatan Sipola, Muhammad Zulfiqar, Gillian Vandekerkhove, Evan W. Warner, Kevin Beja, Matti Nykter, Kim N. Chi, Matti Annala, Martin E. Gleave, Christian K. Kollmansberger, Cameron Herberts, Daniel Khalaf, Daygen Finch, Joanna Vergidis, and Alexander W. Wyatt
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Male ,Cancer Research ,Somatic cell ,medicine.disease_cause ,Circulating Tumor DNA ,Prostate cancer ,chemistry.chemical_compound ,Nitriles ,Phenylthiohydantoin ,Genotype ,Androgen Receptor Antagonists ,medicine ,Humans ,Enzalutamide ,Gene ,Mutation ,business.industry ,medicine.disease ,Androgen receptor ,Clinical trial ,Prostatic Neoplasms, Castration-Resistant ,Oncology ,chemistry ,Benzamides ,Cancer research ,Androstenes ,business - Abstract
Purpose:Cross-resistance renders multiple lines of androgen receptor (AR) signaling inhibitors increasingly futile in metastatic castration-resistant prostate cancer (mCRPC). We sought to determine acquired genomic contributors to cross-resistance.Experimental Design:We collected 458 serial plasma cell-free DNA samples at baseline and progression timepoints from 202 patients with mCRPC receiving sequential AR signaling inhibitors (abiraterone and enzalutamide) in a randomized phase II clinical trial (NCT02125357). We utilized deep targeted and whole-exome sequencing to compare baseline and posttreatment somatic genomic profiles in circulating tumor DNA (ctDNA).Results:Patient ctDNA abundance was correlated across plasma collections and independently prognostic for sequential therapy response and overall survival. Most driver alterations in established prostate cancer genes were consistently detected in ctDNA over time. However, shifts in somatic populations after treatment were identified in 53% of patients, particularly after strong treatment responses. Treatment-associated changes converged upon the AR gene, with an average 50% increase in AR copy number, changes in AR mutation frequencies, and a 2.5-fold increase in the proportion of patients carrying AR ligand binding domain truncating rearrangements.Conclusions:Our data show that the dominant AR genotype continues to evolve during sequential lines of AR inhibition and drives acquired resistance in patients with mCRPC.
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- 2021
20. Abiraterone induces SLCO1B3 expression in prostate cancer via microRNA-579-3p
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Emily N. Risdon, William D. Figg, Douglas K. Price, Kristi Y. Lee, Cindy H. Chau, Roberto H. Barbier, Jonathan D. Strope, and Edel M. McCrea
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Male ,Cell Survival ,Science ,Article ,Androgen deprivation therapy ,Prostate cancer ,Mice ,Solute Carrier Organic Anion Transporter Family Member 1B3 ,In vivo ,Cell Line, Tumor ,microRNA ,LNCaP ,medicine ,Animals ,Humans ,3' Untranslated Regions ,Cell Proliferation ,Cancer ,Multidisciplinary ,Dose-Response Relationship, Drug ,Chemistry ,Prostatic Neoplasms ,Transporter ,Androgen Antagonists ,medicine.disease ,Xenograft Model Antitumor Assays ,In vitro ,Up-Regulation ,Gene Expression Regulation, Neoplastic ,MicroRNAs ,Cancer therapeutic resistance ,Drug Resistance, Neoplasm ,PC-3 Cells ,Cancer research ,Medicine ,Androstenes - Abstract
Understanding mechanisms of resistance to abiraterone, one of the primary drugs approved for the treatment of castration resistant prostate cancer, remains a priority. The organic anion polypeptide 1B3 (OATP1B3, encoded by SLCO1B3) transporter has been shown to transport androgens into prostate cancer cells. In this study we observed and investigated the mechanism of induction of SLCO1B3 by abiraterone. Prostate cancer cells (22Rv1, LNCaP, and VCAP) were treated with anti-androgens and assessed for SLCO1B3 expression by qPCR analysis. Abiraterone treatment increased SLCO1B3 expression in 22Rv1 cells in vitro and in the 22Rv1 xenograft model in vivo. MicroRNA profiling of abiraterone-treated 22Rv1 cells was performed using a NanoString nCounter miRNA panel followed by miRNA target prediction. TargetScan and miRanda prediction tools identified hsa-miR-579-3p as binding to the 3′-untranslated region (3′UTR) of the SLCO1B3. Using dual luciferase reporter assays, we verified that hsa-miR-579-3p indeed binds to the SLCO1B3 3′UTR and significantly inhibited SLCO1B3 reporter activity. Treatment with abiraterone significantly downregulated hsa-miR-579-3p, indicating its potential role in upregulating SLCO1B3 expression. In this study, we demonstrated a novel miRNA-mediated mechanism of abiraterone-induced SLCO1B3 expression, a transporter that is also responsible for driving androgen deprivation therapy resistance. Understanding mechanisms of abiraterone resistance mediated via differential miRNA expression will assist in the identification of potential miRNA biomarkers of treatment resistance and the development of future therapeutics.
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- 2021
21. Stereotactic body radiotherapy for oligoprogressive lesions in metastatic castration‐resistant prostate cancer patients during abiraterone/enzalutamide treatment
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Sadık Muallaoğlu, Cem Onal, Pervin Hurmuz, Fadil Akyol, Ezgi Oymak, Sercan Aksoy, Burak Tilki, Fatih Kose, Gokhan Ozyigit, and Ozan Cem Guler
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Male ,0301 basic medicine ,Oncology ,Cancer Research ,medicine.medical_specialty ,Multivariate analysis ,Urology ,medicine.medical_treatment ,Antineoplastic Agents ,Radiosurgery ,Metastasis ,03 medical and health sciences ,chemistry.chemical_compound ,Prostate cancer ,0302 clinical medicine ,Prostate ,Internal medicine ,Nitriles ,Phenylthiohydantoin ,medicine ,Humans ,Enzalutamide ,Radiology, Nuclear Medicine and imaging ,Neoplasm Metastasis ,Neoplasm Staging ,Univariate analysis ,Chemotherapy ,Radiation ,business.industry ,Middle Aged ,Prostate-Specific Antigen ,Prognosis ,medicine.disease ,Combined Modality Therapy ,Progression-Free Survival ,Prostatic Neoplasms, Castration-Resistant ,Abiraterone ,Treatment Outcome ,030104 developmental biology ,medicine.anatomical_structure ,chemistry ,030220 oncology & carcinogenesis ,Benzamides ,Androstenes ,business ,Stereotactic body radiotherapy - Abstract
Purpose/objective(s) Metastasis- directed therapy (MDT) utilizing stereotactic body radiotherapy (SBRT) for oligoprogressive lesions could provide a delay in next-line systemic treatment (NEST) change while undergoing androgen receptor-targeted agents (ARTA) treatment. We evaluated prognostic factors for prostate cancer-specific survival (PCSS) and progression-free survival (PFS) to characterize patients receiving treatment with ARTA who may benefit from MDT for oligoprogressive lesions. The impact of MDT on delaying NEST and the predictive factors for NEST-free survival (NEST-FS) were also assessed. Materials/methods The clinical data of 54 metastatic castration-resistant prostate cancer patients with 126 oligoprogressive lesions receiving abiraterone (1 g/day) or enzalutamide (160 mg/day) before or after systemic chemotherapy were analyzed. A median of three lesions (range: 1-5) were treated with MDT. The primary end points were PCSS and PFS. The secondary end points were time to switch to NEST and NEST-FS. Results The median follow-up time was 19.1 months. Univariate analysis showed that the number of oligoprogressive lesions treated with SBRT and the time between the start of ARTA treatment and oligoprogression were significant prognostic factors for PCSS, and the timing of ARTA treatment (before or after chemotherapy) and the PSA response after MDT were significant prognostic factors for PFS. Multivariate analysis showed that early MDT for oligoprogressive lesions delivered less than six months after beginning of ARTA [HR = 3.20 (95% CI, 1.12-9.15); P = 0.03] and higher PSA levels after MDT [HR = 1.01 (95% CI 1.00-1.01), P = 0.02] were significant predictors of worse PCSS and PFS. The median total duration of ARTA treatment was 13.8 months. The median time between the start of ARTA treatment and the start of MDT for oligoprogressive lesions was 5.2 months, and MDT extended the ARTA treatment by 8.6 months on average. Thirty-two (59.3%) patients continued ARTA treatment after MDT. ARTA treatment after chemotherapy, early oligoprogression requiring MDT, and lower radiation doses for MDT were independent predictors of NEST-FS in multivariate analysis. Conclusion MDT for oligoprogressive lesions is effective and may provide several benefits compared to switching from ARTA treatment to NEST. Patients with early progression while on ARTAs and inadequate PSA responses after MDT have a greater risk of rapid disease progression and poor survival, which necessitates intensified treatment.
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- 2021
22. Abiraterone suppresses irradiated lung cancer cells-induced angiogenic capacities of endothelial cells
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Tingyan Ruan, Juying Zhou, Junying Xu, and Liping Jiang
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0301 basic medicine ,A549 cell ,Tube formation ,Lung Neoplasms ,Physiology ,Chemistry ,Angiogenesis ,Akt/PKB signaling pathway ,Endothelial Cells ,Cell Biology ,respiratory system ,medicine.disease ,respiratory tract diseases ,03 medical and health sciences ,Prostate cancer ,030104 developmental biology ,0302 clinical medicine ,030220 oncology & carcinogenesis ,Cancer research ,medicine ,Humans ,Androstenes ,MTT assay ,Lung cancer ,PI3K/AKT/mTOR pathway - Abstract
Non-small cell lung cancer (NSCLC) threatens human life globally with high morbidity and mortality and radiotherapy is one of the most effective methods for the treatment of NSCLC. However, it is currently reported that the angiogenesis of tumors can be induced by a low dosage of irradiation. Abiraterone is an oral anti-tumor agent for the treatment of castration-resistant prostate cancer (CRPC). In the present study, the anti-angiogenesis effect of Abiraterone against HUVECs incubated with irradiated lung cancer cell medium will be investigated. The HUVECs were incubated with a cultural medium of the NSCLC cell line-A549, Abiraterone-treated A549 cells, irradiation-treated A549 cells, and Abiraterone and irradiation co-treated A549 cells. The tolerable concentration of Abiraterone against HUVECs was determined using MTT assay. The migration and angiogenesis abilities of HUVECs were evaluated using transwell and tube formation assays, respectively. The expression levels of VEGF, MMP-2, and MMP-9 in the treated HUVECs were detected using qRT-PCR and ELISA. Western blot was used to determine the expressions of p-PI3K and p-AKT. The tolerable concentration of Abiraterone used in the present study was 50 nM. First, the migration rate and numbers of formed tubes were significantly decreased by the A549 medium treated with Abiraterone and elevated by the A549 medium treated with irradiation but greatly suppressed by the co-treatment with Abiraterone. Subsequently, VEGF, MMP-2, and MMP-9 were significantly downregulated by the A549 medium treated with Abiraterone and upregulated by the A549 medium treated with irradiation but greatly inhibited by the co-treatment with Abiraterone. Lastly, the activated PI3K/AKT signaling pathway induced by the A549 medium treated with irradiation was significantly suppressed by the A549 medium treated with both irradiation and Abiraterone. Abiraterone suppressed irradiated lung cancer cells-induced angiogenic capacities of endothelial cells.
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- 2021
23. Endocrine and metabolic effects of an oral contraceptive containing estetrol and drospirenone
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Ingrid Duijkers, Marie Mawet, Christine Klipping, Jean-Michel Foidart, Adriana Bastidas, Catherine Maillard, and Maud Jost
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endocrine system ,medicine.medical_specialty ,Levonorgestrel ,Ethinyl Estradiol ,03 medical and health sciences ,chemistry.chemical_compound ,Follicle-stimulating hormone ,0302 clinical medicine ,Sex hormone-binding globulin ,Sex Hormone-Binding Globulin ,Ethinylestradiol ,Internal medicine ,medicine ,Humans ,030212 general & internal medicine ,030219 obstetrics & reproductive medicine ,medicine.diagnostic_test ,biology ,business.industry ,Estetrol ,Obstetrics and Gynecology ,Estrogens ,Drospirenone ,Contraceptives, Oral, Combined ,Endocrinology ,Reproductive Medicine ,chemistry ,biology.protein ,Androstenes ,Female ,Lipid profile ,Luteinizing hormone ,business ,medicine.drug - Abstract
Objectives To evaluate the effect on endocrine and metabolic parameters of a new combined oral contraceptive (COC) containing estetrol (E4) and drospirenone (DRSP). Study design Randomized, open-label, controlled, 3-arm, parallel study. Healthy subjects received either E4 15 mg/DRSP 3 mg (E4/DRSP) (n = 38), or ethinylestradiol (EE) 30 µg/levonorgestrel (LNG) 150 µg (n = 29), or EE 20 µg/DRSP 3 mg (n = 31) for 6 treatment cycles. Median percentage change from baseline to cycle 3 and to cycle 6 were evaluated for endocrine parameters, liver proteins, lipid profile, and carbohydrate metabolism. Results At cycle 6, E4/DRSP treatment had less effect on gonadotropins (follicle stimulating hormone [FSH] +30.5%, luteinizing hormone [LH] −7.5%) compared to EE/LNG (FSH −84.0%, LH −92.0%) and EE/DRSP (FSH −64.0%, LH −90.0%). With E4/DRSP increases in total cortisol (+26.0%) and cortisol binding globulin ([CBG] (+40.0%) were less compared to EE/LNG (cortisol +109.0%, CBG +152.0%) and EE/DRSP (cortisol +107.0%, CBG +140.0%). Liver proteins, except CRP, increased, but the effect was less pronounced with E4/DRSP for angiotensinogen (+75.0%) compared to EE/LNG (+170.0%) and EE/DRSP (+206.5%) and for sex hormone binding globulin ([SHBG] +55.0%), compared to EE/LNG (+74.0%) and EE/DRSP (+251.0%). E4/DRSP had minimal impact on lipid parameters; the largest effect was observed for triglycerides (+24.0%), which was less compared to EE/LNG (+28.0%) and EE/DRSP (+65.5%). E4/DRSP had no effect on carbohydrate metabolism. Conclusions E4/DRSP treatment has limited effects on endocrine and metabolic parameters. The effects on gonadotropins, cortisol, CBG, angiotensinogen, SHBG and triglycerides were less pronounced compared to EE-containing products. Implications statement Combining E4 15 mg with DRSP 3 mg resulted in a COC with a different metabolic profile in comparison to EE-containing products. The clinical relevance of these findings needs to be further assessed, using clinical endpoints to establish the safety profile of this new COC.
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- 2021
24. Safety of concomitant therapy with radium‐223 and abiraterone or enzalutamide in a real‐world population
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Amanda De Hoedt, Christopher L. Amling, Stephen J. Freedland, Lauren E. Howard, Adriana C. Vidal, William J. Aronson, Christopher J. Kane, Matthew R. Cooperberg, Hanson Zhao, Thomas J. Polascik, Zachary Klaassen, and Martha K. Terris
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Male ,0301 basic medicine ,medicine.medical_specialty ,Combination therapy ,Urology ,Bone Neoplasms ,03 medical and health sciences ,Prostate cancer ,chemistry.chemical_compound ,0302 clinical medicine ,Internal medicine ,Nitriles ,Phenylthiohydantoin ,Concomitant Therapy ,medicine ,Humans ,Enzalutamide ,Veterans Affairs ,Aged ,Veterans ,business.industry ,Hazard ratio ,Middle Aged ,medicine.disease ,Combined Modality Therapy ,Survival Rate ,Prostatic Neoplasms, Castration-Resistant ,030104 developmental biology ,Denosumab ,Oncology ,chemistry ,030220 oncology & carcinogenesis ,Concomitant ,Benzamides ,Androstenes ,business ,Radium ,medicine.drug - Abstract
Background Real-world utilization and outcomes of combination therapy for men with metastatic castrate-resistant prostate cancer (mCRPC) are largely unknown. We evaluated the overall survival (OS) and skeletal-related events (SREs) among men who received radium-223 with or without concomitant abiraterone or enzalutamide in the Veterans Affairs (VA) Health System. Methods We reviewed charts of all mCRPC patients who received radium-223 in the VA from January 2013 to September 2017. We used Cox models to test the association between concomitant therapy versus radium-223 alone on OS and SRE. Sensitivity analyses were performed for concomitant use of denosumab/bisphosphonates. Results Three hundred and eighteen patients treated with radium-223 were identified; 116/318 (37%) received concomitant abiraterone/enzalutamide. Two hundred and seventy-seven (87%) patients died during follow-up. Patients who received concomitant therapy were younger at radium-223 initiation (median age 68 vs. 70, p = .027) and had a longer follow-up (median 29.5 vs. 17.9 months, p = .030). There was no OS benefit for those on concomitant therapy (hazard ratio [HR]: 0.87, 95% confidence interval [CI]: 0.67-1.12, p = .28). There was a trend for an increased SRE risk for patients on concomitant therapy (HR: 1.87, 95% CI: 0.96-3.61, p = .066), but this was not significant. When analyses were limited to men using bone heath agents, similar results were seen for OS (HR: 0.86, 95% CI 0.64-1.15, p = .30) and SRE (HR: 2.36, 95% CI: 0.94-5.94, p = .068). Conclusions Despite the common use of concomitant therapy in this real-world study, there was no difference in OS among mCRPC patients. A nonsignificant increased SRE risk was observed. Further work needs to evaluate the optimal sequence, timing, and safety of combination therapies.
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- 2021
25. Antihormone treatment differentially regulates PSA secretion, PSMA expression and 68Ga–PSMA uptake in LNCaP cells
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Thomas Mayr, Michael Meisenheimer, Ralph A. Bundschuh, Birgit Stoffel-Wagner, Markus Essler, Stefan Kürpig, Ramona C. Dolscheid-Pommerich, Glen Kristiansen, Michael Muders, and C S Mathy
- Subjects
Glutamate Carboxypeptidase II ,Male ,Cancer Research ,Programmed cell death ,VPC-13566 ,Androgen antagonist ,Gallium Radioisotopes ,Prostate-specific membrane antigen ,Adenocarcinoma ,urologic and male genital diseases ,030218 nuclear medicine & medical imaging ,03 medical and health sciences ,Prostate cancer ,0302 clinical medicine ,Downregulation and upregulation ,In vivo ,Cell Line, Tumor ,Positron Emission Tomography Computed Tomography ,LNCaP ,Glutamate carboxypeptidase II ,medicine ,Humans ,Secretion ,Abiraterone ,Edetic Acid ,Gallium Isotopes ,Secretory Pathway ,Chemistry ,Prostatic Neoplasms ,Androgen Antagonists ,General Medicine ,Prostate-Specific Antigen ,medicine.disease ,In vitro ,Gene Expression Regulation, Neoplastic ,Oncology ,030220 oncology & carcinogenesis ,Antigens, Surface ,PC-3 Cells ,Cancer research ,Androstenes ,[68Ga]Ga-PSMA-11 ,Original Article – Cancer Research ,Oligopeptides - Abstract
Background In recent years, a variety of innovative therapeutics for castration-resistant prostate cancer have been developed, including novel anti-androgenic drugs, such as abiraterone or VPC-13566. Therapeutic monitoring of these pharmaceuticals is performed either by measuring PSA levels in serum or by imaging. PET using PSMA ligands labeled with Fluor-18 or Gallium-68 is the most sensitive and specific imaging modality for detection of metastases in advanced prostate cancer. To date, it remains unclear how PSMA expression is modulated by anti-hormonal treatment and how it correlates with PSA secretion. Methods We analyzed modulation of PSMA-mRNA and protein expression, 68Ga–PSMA uptake and regulation of PSA secretion by abiraterone or VPC-13566 in LNCaP cells in vitro. Results We found that abiraterone and VPC-13566 upregulate PSMA protein and mRNA expression but block PSA secretion in LNCaP cells. Both anti-androgens also enhanced 68Ga–PSMA uptake normalized by the number of cells, whereas abiraterone and VPC-13566 reduced 68Ga–PSMA uptake in total LNCaP monolayers treated due to cell death. Conclusion Our data indicate that PSA secretion and PSMA expression are differentially regulated upon anti-androgen treatment. This finding might be important for the interpretation of 68Ga–PSMA PET images in monitoring therapies with abiraterone and VPC-13566 in prostate cancer patients, but needs to be validated in vivo.
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- 2021
26. SEOM clinical guidelines for the treatment of advanced prostate cancer (2020)
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González-del-Alba, Aránzazu, Méndez-Vidal, M. J., Vazquez, S., Castro, E., Climent, Miguel Ángel, Gallardo, Eduard, Gonzalez-Billalabeitia, Enrique, Lorente, D., Maroto Rey, Pablo., Arranz Alija, Jose Ángel, and Universitat Autònoma de Barcelona
- Subjects
Male ,Oncology ,Cancer Research ,Genes, BRCA2 ,Genes, BRCA1 ,Docetaxel ,Medical Oncology ,Piperazines ,Androgen ,Prostate cancer ,chemistry.chemical_compound ,0302 clinical medicine ,030212 general & internal medicine ,Societies, Medical ,Randomized Controlled Trials as Topic ,Apalutamide ,General Medicine ,Combined Modality Therapy ,Prostatic Neoplasms, Castration-Resistant ,Darolutamide ,Thiohydantoins ,Cabazitaxel ,030220 oncology & carcinogenesis ,Benzamides ,Hormonal therapy ,Androstenes ,medicine.drug ,medicine.medical_specialty ,Clinical Guides in Oncology ,Antineoplastic Agents ,Olaparib ,03 medical and health sciences ,Internal medicine ,Nitriles ,Phenylthiohydantoin ,medicine ,Humans ,Enzalutamide ,Castration ,Genetic Testing ,Radiotherapy ,business.industry ,Research ,Molecular ,Prostatic Neoplasms ,Androgen Antagonists ,medicine.disease ,chemistry ,Spain ,Phthalazines ,business ,Orchiectomy ,Biomarkers - Abstract
The treatment of advanced prostate cancer has evolved due to recent advances in molecular research and new drug development. Dynamic aberrations in the androgen receptor, DNA repair genes, PTEN-PI3K, and other pathways drive the behavior of advanced prostate cancer allowing a better selection of therapies in each patient. Tumor testing for BRCA1 and BRCA2 is recommended for patients with metastatic prostate cancer, also considering a broad panel to guide decisions and genetic counseling. In symptomatic metastatic patients, castration should be stared to palliate symptoms and prolong survival. In high-risk or high-volume metastatic hormone-naïve patients, castration should be combined with docetaxel, abiraterone, enzalutamide or apalutamide. Radiotherapy to the primary tumor combined with systemic therapy is recommended in low-volume mHNPC patients. In patients with non-metastatic castration-resistant tumors, risk stratification can define the frequency of imaging. Adding enzalutamide, darolutamide or apalutamide to these patients prolongs metastasis-free and overall survival, but potential adverse events need to be taken into consideration. The choice of docetaxel, abiraterone or enzalutamide for treating metastatic castration-resistant patients depends on previous therapies, with cabazitaxel being also recommended after docetaxel. Olaparib is recommended in BRCA1/BRCA2 mutated castration-resistant patients after progression on at least one new hormonal therapy. Aggressive variants of prostate cancer respond to platinum-based chemotherapy. To optimize treatment efficiency, oncologists should incorporate all of these advances into an overall therapeutic strategy.
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- 2021
27. Cost-effectiveness analysis of cabazitaxel for metastatic castration resistant prostate cancer after docetaxel and androgen-signaling-targeted inhibitor resistance
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Qiu Li, Dan Xie, and Pengfei Zhang
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Oncology ,Male ,Cancer Research ,medicine.medical_specialty ,Cost effectiveness ,Cost-Benefit Analysis ,Docetaxel ,lcsh:RC254-282 ,03 medical and health sciences ,Prostate cancer ,chemistry.chemical_compound ,0302 clinical medicine ,Internal medicine ,Antineoplastic Combined Chemotherapy Protocols ,Genetics ,Clinical endpoint ,Enzalutamide ,Medicine ,Humans ,030212 general & internal medicine ,Abiraterone ,Survival analysis ,health care economics and organizations ,Cabazitaxel ,business.industry ,medicine.disease ,Prognosis ,lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,Survival Rate ,Prostatic Neoplasms, Castration-Resistant ,chemistry ,Drug Resistance, Neoplasm ,030220 oncology & carcinogenesis ,Androstenes ,Taxoids ,Cost-effectiveness ,Quality-Adjusted Life Years ,business ,Progressive disease ,medicine.drug ,Research Article ,Follow-Up Studies - Abstract
Background The aim of our study was to evaluate the cost-effectiveness of cabazitaxel versus abiraterone or enzalutamide in patients with metastatic castration-resistant prostate cancer (mCRPC) previously treated with docetaxel who had progression within 12 months while receiving an alternative inhibitor (abiraterone or enzalutamide) from a US payer’s perspective. Methods To conduct the cost-effectiveness analysis, a Markov decision model was established. Three health states (progression-free survival (PFS), progressive disease (PD) and death) were included, and the incremental cost-effectiveness ratio (ICER) was regarded as the primary endpoint. The willingness-to-pay (WTP) threshold was set at $100,000.00/quality-adjusted life year (QALY), and discounted rates were set at 3% annually. Efficacy data were derived from the CARD trial and Weibull distribution curves were modeled to fit the survival curves. The robustness of the analysis was tested with a series of one-way sensitivity analyses and probabilistic sensitivity analyses. Results Overall, the incremental effectiveness and cost of cabazitaxel versus androgen-signaling-targeted inhibitors (ASTIs) were 0.16 QALYs and $49,487.03, respectively, which yielded an ICER of $309,293.94/QALY. Our model was mostly sensitive to the duration of PFS in the cabazitaxel group, cost of cabazitaxel and utility of the PFS state. At a WTP threshold of $100,000.00/QALY, cabazitaxel was the dominant strategy in 0% of the simulations. Conclusions Cabazitaxel is unlikely to be a cost-effective treatment option compared with ASTIs in patients with mCRPC previously treated with docetaxel who had progression within 12 months while receiving ASTIs.
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- 2021
28. Androgen receptor gain in circulating free DNA and splicing variant 7 in exosomes predict clinical outcome in CRPC patients treated with abiraterone and enzalutamide
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Giuseppe Schepisi, Stefania Crucitta, Vincenza Conteduca, Chiara Casadei, Federico Cucchiara, C. Lolli, M. Del Re, Giorgia Gurioli, Giuliana Restante, Romano Danesi, and U. De Giorgi
- Subjects
0301 basic medicine ,Male ,Cancer Research ,medicine.medical_specialty ,Cancer therapy ,Urology ,Predictive markers ,Exosomes ,Article ,03 medical and health sciences ,chemistry.chemical_compound ,Prostate cancer ,0302 clinical medicine ,Text mining ,Castration Resistance ,Nitriles ,Phenylthiohydantoin ,medicine ,Biomarkers, Tumor ,Enzalutamide ,Humans ,Liquid biopsy ,Aged ,Retrospective Studies ,Aged, 80 and over ,business.industry ,Standard treatment ,Middle Aged ,medicine.disease ,Prognosis ,Androgen receptor ,Survival Rate ,Abiraterone ,Alternative Splicing ,Prostatic Neoplasms, Castration-Resistant ,030104 developmental biology ,Oncology ,chemistry ,Drug Resistance, Neoplasm ,Receptors, Androgen ,030220 oncology & carcinogenesis ,Benzamides ,Androstenes ,business ,Cell-Free Nucleic Acids ,Follow-Up Studies - Abstract
Background Androgen receptor (AR) signaling inhibitors represent the standard treatment in metastatic castration resistance prostate cancer (mCRPC) patients. However, some patients display a primary resistance, and several studies investigated the role of the AR as a predictive biomarker of response to treatment. This study is aimed to evaluate the role of AR in liquid biopsy to predict clinical outcome to AR signaling inhibitors in mCRPC patients. Methods Six milliliters of plasma samples were collected before first-line treatment with abiraterone or enzalutamide. Circulating free DNA (cfDNA) and exosome-RNA were isolated for analysis of AR gain and AR splice variant 7 (AR-V7), respectively, by digital droplet PCR. Results Eighty-four mCRPC patients received abiraterone (n = 40) or enzalutamide (n = 44) as first-line therapy. Twelve patients (14.3%) presented AR gain and 30 (35.7%) AR-V7+ at baseline. Median progression-free survival (PFS) and overall survival (OS) were significantly longer in AR-V7− vs AR-V7+ patients (24.3 vs 5.4 months, p p = 0.0001, respectively). Patients carrying the AR gain had a median PFS of 4.8 vs 24.3 months for AR normal patients (p AR normal vs patients with AR gain (not reached vs 8.17 months, p AR gain was observed (r = 0.28; p = 0.01). The AR gain/AR-V7 combined analysis confirmed a strong predictive effect for biomarkers combination vs patients without any AR aberration (PFS 3.8 vs 28 month, respectively; OS 6.1 vs not reached, respectively; p Conclusions The present study demonstrates that cfDNA and exosome-RNA are both a reliable source of AR variants and their combined detection in liquid biopsy predicts resistance to AR signaling inhibitors.
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- 2021
29. Evaluation of the effect of a new oral contraceptive containing estetrol and drospirenone on hemostasis parameters
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Jan Rosing, Marie Mawet, Maud Jost, Christine Klipping, Catherine Maillard, Jonathan Douxfils, Jean-Michel Foidart, I.J.M. Duijkers, Virginie Kinet, RS: Carim - B01 Blood proteins & engineering, and Biochemie
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Ethinyl Estradiol ,activated protein c resistance ,chemistry.chemical_compound ,0302 clinical medicine ,Sex hormone-binding globulin ,Sex Hormone-Binding Globulin ,Medicine ,Levonorgestrel ,030212 general & internal medicine ,RISK ,030219 obstetrics & reproductive medicine ,biology ,Estetrol ,Obstetrics and Gynecology ,Middle Aged ,Contraceptives, Oral, Combined ,Contraception ,Androstenes ,Female ,medicine.drug ,Adult ,VENOUS THROMBOSIS ,medicine.medical_specialty ,Adolescent ,medicine.drug_class ,PROFILE ,Young Adult ,03 medical and health sciences ,Drospirenone ,Ethinylestradiol ,Internal medicine ,Humans ,CYCLE ,Menstrual Cycle ,Hemostasis ,levonorgestrel ,business.industry ,Estrogens ,medicine.disease ,Endocrinology ,Reproductive Medicine ,chemistry ,Estrogen ,biology.protein ,Activated protein C resistance ,business - Abstract
Objective: To assess the effect on hemostasis parameters of a new combined oral contraceptive (COC). Study design: In this randomized, single centre, open-label, exploratory study, healthy women received either 15 mg estetrol/3 mg drospirenone (E4/DRSP) (n = 39), 30 mcg ethinylestradiol/150 mcg levonorgestrel (EE/LNG) (n = 30), or 20 mcg ethinylestradiol/3 mg drospirenone (EE/DRSP) (n = 32) for six 28day cycles. Blood was collected at baseline, cycle 3, and cycle 6. Median change from baseline was evaluated for procoagulant, anticoagulant, and fibrinolytic parameters, and for sex hormone-binding globulin (SHBG).Results: Median change of endogenous thrombin potential (ETP) based activated protein C sensitivity resistance (APCr) at cycle 6 was +30% for E4/DRSP, +165% for EE/LNG (p-value
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- 2020
30. Cost-Effectiveness of Metastasis-Directed Therapy in Oligorecurrent Hormone-Sensitive Prostate Cancer
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Amar U. Kishan, Phuoc T. Tran, Robert E. Reiter, Piet Ost, Daniel E. Spratt, Nicholas G. Nickols, Felix Y. Feng, Bridget F. Koontz, Neil R. Parikh, Ryan Phillips, Michael L. Steinberg, Eric M. Chang, Ann C. Raldow, Matthew Rettig, Neha Vapiwala, and Curtiland Deville
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Male ,Oncology ,Cancer Research ,medicine.medical_specialty ,Time Factors ,Antineoplastic Agents, Hormonal ,Cost effectiveness ,Cost-Benefit Analysis ,Docetaxel ,Radiosurgery ,Systemic therapy ,030218 nuclear medicine & medical imaging ,Androgen deprivation therapy ,03 medical and health sciences ,chemistry.chemical_compound ,Prostate cancer ,0302 clinical medicine ,Prednisone ,Internal medicine ,Confidence Intervals ,medicine ,Humans ,Radiology, Nuclear Medicine and imaging ,Salvage Therapy ,Radiation ,business.industry ,Abiraterone acetate ,Prostatic Neoplasms ,Androgen Antagonists ,medicine.disease ,Comorbidity ,Markov Chains ,chemistry ,030220 oncology & carcinogenesis ,Androstenes ,Quality-Adjusted Life Years ,business ,Monte Carlo Method ,medicine.drug - Abstract
Purpose Oligorecurrent prostate cancer has historically been treated with indefinite androgen deprivation therapy (ADT), although many patients and providers opt to defer this treatment at the time of recurrence given quality-of-life and/or comorbidity considerations. Recently, metastasis-directed therapy (MDT) has emerged as a potential intermediary between surveillance and immediate continuous ADT. Simultaneously, advanced systemic therapy in addition to ADT has also been shown to improve survival in metastatic hormone-sensitive disease. This study aimed to compare the cost-effectiveness of treating oligorecurrent patients with upfront MDT before standard-of-care systemic therapy. Methods and Materials A Markov-based cost-effectiveness analysis was constructed comparing 3 strategies: (1) upfront MDT → salvage abiraterone acetate plus prednisone (AAP) + ADT → salvage docetaxel + ADT; (2) upfront AAP + ADT → salvage docetaxel + ADT; and (3) upfront docetaxel + ADT → salvage AAP + ADT. Transition probabilities and utilities were derived from the literature. Using a 10-year time horizon and willingness-to-pay threshold of $100,000/quality-adjusted life year (QALY), net monetary benefit values were subsequently calculated for each treatment strategy. Results At 10 years, the base case revealed a total cost of $141,148, $166,807, and $136,154 with QALYs of 4.63, 4.89, and 4.00, respectively, reflecting a net monetary benefit of $322,240, $322,018, and $263,407 for upfront MDT, upfront AAP + ADT, and upfront docetaxel + ADT, respectively. In the probabilistic sensitivity analysis using a Monte Carlo simulation (1,000,000 simulations), upfront MDT was the cost-effective strategy in 53.6% of simulations. The probabilistic sensitivity analysis revealed 95% confidence intervals for cost ($75,914-$179,862, $124,431-$223,892, and $103,298-$180,617) and utility in QALYs (3.85-6.12, 3.91-5.86, and 3.02-5.22) for upfront MDT, upfront AAP + ADT, and upfront docetaxel + ADT, respectively. Conclusions At 10 years, upfront MDT followed by salvage AAP + ADT, is comparably cost-effective compared with upfront standard-of-care systemic therapy and may be considered a viable treatment strategy, especially in patients wishing to defer systemic therapy for quality-of-life or comorbidity concerns. Additional studies are needed to determine whether MDT causes a sustained meaningful delay in disease natural history and whether any benefit exists in combining MDT with upfront advanced systemic therapy.
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- 2020
31. A Phase Ib/IIa Study of the Pan-BET Inhibitor ZEN-3694 in Combination with Enzalutamide in Patients with Metastatic Castration-resistant Prostate Cancer
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Sarah Attwell, David M. Nanus, Eric Campeau, Sanjay Lakhotia, Margo Snyder, Michael T. Schweizer, Lisa Bauman, Rahul Aggarwal, Allan J. Pantuck, Joshi J. Alumkal, Felix Y. Feng, Elisabeth I. Heath, Eric J. Small, Wassim Abida, and Karen Norek
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Male ,0301 basic medicine ,Cancer Research ,Drug Resistance ,Castration-Resistant ,Androgen ,chemistry.chemical_compound ,Prostate cancer ,0302 clinical medicine ,Receptors ,Antineoplastic Combined Chemotherapy Protocols ,80 and over ,Neoplasm Metastasis ,Prospective cohort study ,Cancer ,Prostate Cancer ,Middle Aged ,Progression-Free Survival ,Treatment Outcome ,Oncology ,Tolerability ,6.1 Pharmaceuticals ,030220 oncology & carcinogenesis ,Benzamides ,Androstenes ,Urologic Diseases ,medicine.medical_specialty ,Oncology and Carcinogenesis ,Urology ,Antineoplastic Agents ,Disease-Free Survival ,03 medical and health sciences ,Clinical Research ,Nitriles ,Phenylthiohydantoin ,medicine ,Humans ,Enzalutamide ,Oncology & Carcinogenesis ,Dosing ,Progression-free survival ,Aged ,business.industry ,Prostatic Neoplasms ,Evaluation of treatments and therapeutic interventions ,medicine.disease ,Androgen receptor ,Clinical trial ,030104 developmental biology ,chemistry ,Neoplasm ,business - Abstract
Purpose:ZEN-3694 is a bromodomain extraterminal inhibitor (BETi) with activity in androgen-signaling inhibitor (ASI)-resistant models. The safety and efficacy of ZEN-3694 plus enzalutamide was evaluated in a phase Ib/IIa study in metastatic castration-resistant prostate cancer (mCRPC).Patients and Methods:Patients had progressive mCRPC with prior resistance to abiraterone and/or enzalutamide. 3+3 dose escalation was followed by dose expansion in parallel cohorts (ZEN-3694 at 48 and 96 mg orally once daily, respectively).Results:Seventy-five patients were enrolled (N = 26 and 14 in dose expansion at low- and high-dose ZEN-3694, respectively). Thirty (40.0%) patients were resistant to abiraterone, 34 (45.3%) to enzalutamide, and 11 (14.7%) to both. ZEN-3694 dosing ranged from 36 to 144 mg daily without reaching an MTD. Fourteen patients (18.7%) experienced grade ≥3 toxicities, including three patients with grade 3 thrombocytopenia (4%). An exposure-dependent decrease in whole-blood RNA expression of BETi targets was observed (up to fourfold mean difference at 4 hours post–ZEN-3694 dose; P ≤ 0.0001). The median radiographic progression-free survival (rPFS) was 9.0 months [95% confidence interval (CI), 4.6–12.9] and composite median radiographic or clinical progression-free survival (PFS) was 5.5 months (95% CI, 4.0–7.8). Median duration of treatment was 3.5 months (range, 0–34.7+). Lower androgen receptor (AR) transcriptional activity in baseline tumor biopsies was associated with longer rPFS (median rPFS 10.4 vs. 4.3 months).Conclusions:ZEN-3694 plus enzalutamide demonstrated acceptable tolerability and potential efficacy in patients with ASI-resistant mCRPC. Further prospective study is warranted including in mCRPC harboring low AR transcriptional activity.
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- 2020
32. Blood-based gene expression signature associated with metastatic castrate-resistant prostate cancer patient response to abiraterone plus prednisone or enzalutamide
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Qi Long, Naomi B. Haas, Michael J. LaRiviere, Eun Jeong Min, Yauheniya Cherkas, Jeremy O. Jones, Sumanta K. Pal, Erica L. Carpenter, David J. Vaughn, Samantha L. Savitch, Taylor A. Black, Stephanie S. Yee, Kathryn E. Wellen, Brad Foulk, Miaoling He, Thomas H. Buckingham, Steven Gross, Ravi K. Amaravadi, Denis Smirnov, Jaymala Patel, Karl Calara-Nielsen, and Krishna J. Majmundar
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Male ,Oncology ,Cancer Research ,medicine.medical_specialty ,Urology ,030232 urology & nephrology ,Bone Neoplasms ,03 medical and health sciences ,Prostate cancer ,chemistry.chemical_compound ,0302 clinical medicine ,Circulating tumor cell ,Prednisone ,Internal medicine ,Nitriles ,Phenylthiohydantoin ,Biomarkers, Tumor ,medicine ,Humans ,Enzalutamide ,Prospective Studies ,Antiandrogen Therapy ,Prospective cohort study ,Testosterone ,Aged ,Retrospective Studies ,Aged, 80 and over ,business.industry ,Androgen Antagonists ,Middle Aged ,Neoplastic Cells, Circulating ,Prognosis ,medicine.disease ,Survival Rate ,Prostatic Neoplasms, Castration-Resistant ,chemistry ,Lymphatic Metastasis ,030220 oncology & carcinogenesis ,Benzamides ,Cohort ,Androstenes ,Transcriptome ,business ,Follow-Up Studies ,medicine.drug - Abstract
Precision medicine approaches for managing patients with metastatic castrate-resistant prostate cancer (mCRPC) are lacking. Non-invasive approaches for molecular monitoring of disease are urgently needed, especially for patients suffering from bone metastases for whom tissue biopsy is challenging. Here we utilized baseline blood samples to identify mCRPC patients most likely to benefit from abiraterone plus prednisone (AAP) or enzalutamide. Baseline blood samples were collected for circulating tumor cell (CTC) enumeration and qPCR-based gene expression analysis from 51 men with mCRPC beginning treatment with abiraterone or enzalutamide. Of 51 patients (median age 68 years [51–82]), 22 received AAP (abiraterone 1000 mg/day plus prednisone 10 mg/day) and 29 received enzalutamide (160 mg/day). The cohort was randomly divided into training (n = 37) and test (n = 14) sets. Baseline clinical variables (Gleason score, PSA, testosterone, and hemoglobin), CTC count, and qPCR-based gene expression data for 141 genes/isoforms in CTC-enriched blood were analyzed with respect to overall survival (OS). Genes with expression most associated with OS included MSLN, ARG2, FGF8, KLK3, ESRP2, NPR3, CCND1, and WNT5A. Using a Cox-elastic net model for our test set, the 8-gene expression signature had a c-index of 0.87 (95% CI [0.80, 0.94]) and was more strongly associated with OS than clinical variables or CTC count alone, or a combination of the three variables. For patients with a low-risk vs. high-risk gene expression signature, median OS was not reached vs. 18 months, respectively (HR 5.32 [1.91–14.80], p = 0.001). For the subset of 41 patients for whom progression-free survival (PFS) data was available, the median PFS for patients with a low-risk vs high-risk gene expression signature was 20 vs. 5 months, respectively (HR 2.95 [1.46–5.98], p = 0.003). If validated in a larger prospective study, this test may predict patients most likely to benefit from second-generation antiandrogen therapy.
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- 2020
33. The effect of chemotherapy on the exposure-response relation of abiraterone in metastatic castration-resistant prostate cancer
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Rob ter Heine, Inge M. van Oort, Guillemette E. Benoist, Nielka P. van Erp, Niven Mehra, Joanneke K Overbeek, Rogier Donders, and Emmy Boerrigter
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Oncology ,Male ,medicine.medical_specialty ,medicine.medical_treatment ,Abiraterone Acetate ,chemistry.chemical_compound ,Prostate cancer ,Pharmacokinetics ,Internal medicine ,Antineoplastic Combined Chemotherapy Protocols ,Urological cancers Radboud Institute for Molecular Life Sciences [Radboudumc 15] ,medicine ,Humans ,Pharmacology (medical) ,Exposure response ,Retrospective Studies ,Pharmacology ,Chemotherapy ,business.industry ,Proportional hazards model ,Other Research Radboud Institute for Health Sciences [Radboudumc 0] ,Abiraterone acetate ,medicine.disease ,Abiraterone ,Prostatic Neoplasms, Castration-Resistant ,Treatment Outcome ,lnfectious Diseases and Global Health Radboud Institute for Health Sciences [Radboudumc 4] ,chemistry ,Urological cancers Radboud Institute for Health Sciences [Radboudumc 15] ,Toxicity ,Prednisone ,Androstenes ,business - Abstract
Contains fulltext : 248309.pdf (Publisher’s version ) (Open Access) AIMS: To assess whether the exposure-response relation for abiraterone is different in pre-chemotherapy patients compared to post-chemotherapy patients with metastatic castration-resistant prostate cancer (mCRPC). METHODS: Data were collected from three clinical studies in mCRPC patients treated with abiraterone acetate. Cox regression analysis was used to determine the relation between abiraterone exposure and survival (progression-free survival [PFS] and overall survival [OS]). An interaction term was used to test whether chemotherapy pretreatment was an effect modifier. To investigate the effect of the previously defined exposure threshold of 8.4 ng/mL on survival, Kaplan-Meier analysis was used. RESULTS: In total, 98 mCRPC patients were included, of which 78 were pre-chemotherapy and 20 were post-chemotherapy patients. Chemotherapy pretreatment in mCRPC setting appears to be an effect modifier. In pre-chemotherapy patients, no significant association between abiraterone exposure and survival was observed (HR 0.68 [95% CI 0.42-1.10], P = .12 and HR 0.85 [95% CI 0.46-1.60], P = .61, PFS and OS, respectively) and no longer survival was seen for patients with an abiraterone exposure above the predefined threshold. In contrast, a significant association was seen in post-chemotherapy patients (HR 0.30 [95% CI 0.12-0.74], P = .01 and HR 0.38 [95% CI 0.18-0.82] P = .01, PFS and OS, respectively), with an increased survival when exposed above this threshold. CONCLUSION: Chemotherapy pretreatment in mCRPC setting modifies the abiraterone exposure-response relation. No relation between abiraterone exposure and survival was seen for pre-chemotherapy patients. Therefore, potentially lower doses can be used in this setting to prevent overtreatment and reduce financial toxicity.
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- 2022
34. Hospitalization for adverse events under abiraterone or enzalutamide exposure in real-world setting: a French population-based study on prostate cancer patients
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Boris Campillo-Gimenez, Emmanuel Oger, André Happe, Romain Mathieu, Lucie-Marie Scailteux, Fabien Despas, Sandrine Kerbrat, Sébastien Vincendeau, Emmanuel Nowak, Frédéric Balusson, CHU Pontchaillou [Rennes], Recherche en Pharmaco-épidémiologie et Recours aux Soins (REPERES), Université de Rennes (UR)-École des Hautes Études en Santé Publique [EHESP] (EHESP), Centre d'investigation clinique de Toulouse (CIC 1436), Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Pôle Santé publique et médecine publique [CHU Toulouse], Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Laboratoire Traitement du Signal et de l'Image (LTSI), Université de Rennes (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM), CRLCC Eugène Marquis (CRLCC), Institut de recherche en santé, environnement et travail (Irset), Université d'Angers (UA)-Université de Rennes (UR)-École des Hautes Études en Santé Publique [EHESP] (EHESP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), École des Hautes Études en Santé Publique [EHESP] (EHESP), Pharmaco-Épidémiologie des Produits de Santé (PEPS), CIC Brest, Université de Brest (UBO)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Hôpital de la Cavale Blanche, Centre Hospitalier Régional Universitaire de Brest (CHRU Brest), Centre Régional de Pharmacovigilance (CRPV), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), French Drugs Agency, National Health Insurance, Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-École des Hautes Études en Santé Publique [EHESP] (EHESP), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-CHU Toulouse [Toulouse]-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES), Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique )-Institut National de la Santé et de la Recherche Médicale (INSERM)-École des Hautes Études en Santé Publique [EHESP] (EHESP)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Université d'Angers (UA), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Pôle Santé publique et médecine publique [CHU Toulouse], and Jonchère, Laurent
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Male ,safety ,medicine.medical_specialty ,030204 cardiovascular system & hematology ,Rate ratio ,QT interval ,Brain Ischemia ,03 medical and health sciences ,Prostate cancer ,chemistry.chemical_compound ,0302 clinical medicine ,Internal medicine ,abiraterone ,Atrial Fibrillation ,Nitriles ,Phenylthiohydantoin ,Pharmacovigilance ,medicine ,Humans ,Enzalutamide ,castration-resistant prostate cancer ,Pharmacology (medical) ,liver test monitoring ,Adverse effect ,Pharmacology ,[SDV.IB] Life Sciences [q-bio]/Bioengineering ,enzalutamide ,business.industry ,Atrial fibrillation ,medicine.disease ,adverse events ,3. Good health ,Hospitalization ,Stroke ,Prostatic Neoplasms, Castration-Resistant ,Treatment Outcome ,chemistry ,acute kidney injury ,030220 oncology & carcinogenesis ,Heart failure ,Benzamides ,Androstenes ,[SDV.IB]Life Sciences [q-bio]/Bioengineering ,business - Abstract
International audience; Aims - Safety profiles of abiraterone and enzalutamide rely mainly on Phase III clinical trials. Our objective was to estimate the incidence rate ratio (IRR) for certain adverse events leading in real life to hospitalization (atrial fibrillation, acute heart failure, ischaemic heart disease, acute kidney injury [AKI], ischaemic stroke, torsade de pointe/QT interval prolongation, hepatitis and seizure), comparing abiraterone to enzalutamide. We also set out to discuss previously identified safety signals. Method - Using the French National Health Insurance System database, all patients newly exposed to abiraterone or enzalutamide between 2013 and 2017 and followed until 31 December 2018 were targeted. IRRs for each event were estimated using a Poisson model in a sub-population of patients without contraindications or precautions for use for either treatment. Results - Among 11 534 new users of abiraterone and enzalutamide, AKI (IRR 1.42, 95% CI: 1.01-2.00), liver monitoring suggestive of hepatic damage (IRR 3.06, 95% CI: 2.66-3.53) and atrial fibrillation (IRR 1.12, 95% CI: 1.05-1.19) were significantly more often observed with abiraterone than with enzalutamide. Conclusion - Our study provides knowledge on abiraterone and enzalutamide real-life safety profiles, especially for events leading to hospitalization. Despite several limitations, including the lack of clinical data, the safety signal for AKI under abiraterone is in line with results of an analysis of the French pharmacovigilance database, which requires further specific investigations. Enlightening the clinicians' therapeutic choices for patients treated for prostate cancer, our study should lead to clinicians being cautious in the use of abiraterone.
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- 2022
35. Impact of antiandrogen withdrawal syndrome in castration‐resistant prostate cancer patients treated with abiraterone or enzalutamide
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Eiji Kashiwagi, Masaki Shiota, Seiji Naito, Junichi Inokuchi, Masatoshi Eto, Asako Machidori, Ario Takeuchi, Keisuke Monji, Tatsuro Abe, Ryosuke Takahashi, and Akira Yokomizo
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Male ,Oncology ,medicine.medical_specialty ,Bicalutamide ,medicine.drug_class ,Urology ,030232 urology & nephrology ,urologic and male genital diseases ,Antiandrogen ,03 medical and health sciences ,Prostate cancer ,chemistry.chemical_compound ,0302 clinical medicine ,Internal medicine ,Nitriles ,Phenylthiohydantoin ,medicine ,Humans ,Enzalutamide ,business.industry ,Hazard ratio ,Androgen Antagonists ,Prostate-Specific Antigen ,medicine.disease ,Androgen ,Androgen receptor ,Prostatic Neoplasms, Castration-Resistant ,Treatment Outcome ,Castration ,chemistry ,030220 oncology & carcinogenesis ,Benzamides ,Androstenes ,business ,medicine.drug - Abstract
Objectives To assess the impact of antiandrogen withdrawal syndrome after bicalutamide withdrawal in castration-resistant prostate cancer patients treated with androgen receptor-axis targeted agents. Methods The study cohort comprised 94 patients treated with abiraterone (n = 34) or enzalutamide (n = 60) as a first-line androgen receptor-axis targeted agent for castration-resistant prostate cancer despite combined androgen blockade by castration with bicalutamide as the first-line therapy. The association between clinicopathological factors (including antiandrogen withdrawal syndrome) and therapeutic outcome after using abiraterone and enzalutamide was investigated. Results The decline in the prostate-specific antigen level after use of abiraterone or enzalutamide was comparable between patients with and without antiandrogen withdrawal syndrome. Antiandrogen withdrawal syndrome (hazard ratio 3.84, 95% confidence interval 1.29-11.45; P = 0.016) was associated with a higher risk of progression on multivariate analysis, but not all-cause death after abiraterone use. Progression-free survival and overall survival after enzalutamide use did not differ between patients with and without antiandrogen withdrawal syndrome. Conclusions The present data suggest a modest therapeutic efficacy of abiraterone in castration-resistant prostate cancer patients with anti-androgen withdrawal syndrome after bicalutamide withdrawal.
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- 2020
36. Adherence and out‐of‐pocket costs among Medicare beneficiaries who are prescribed oral targeted therapies for advanced prostate cancer
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Megan E.V. Caram, Mary K. Oerline, Lindsey A. Herrel, Vahakn B. Shahinian, Samuel R. Kaufman, Parth K. Modi, Stacie B. Dusetzina, Ted A. Skolarus, and Brent K. Hollenbeck
- Subjects
Male ,Cancer Research ,medicine.medical_specialty ,Referral ,Medicare Part D ,Administration, Oral ,Antineoplastic Agents ,Article ,Drug Costs ,Insurance Coverage ,Medication Adherence ,03 medical and health sciences ,Prostate cancer ,chemistry.chemical_compound ,0302 clinical medicine ,Internal medicine ,Nitriles ,Phenylthiohydantoin ,medicine ,Humans ,Enzalutamide ,030212 general & internal medicine ,Medical prescription ,Socioeconomic status ,Aged ,Retrospective Studies ,Aged, 80 and over ,business.industry ,Medicare beneficiary ,Prostatic Neoplasms ,Retrospective cohort study ,medicine.disease ,United States ,Oncology ,chemistry ,030220 oncology & carcinogenesis ,Benzamides ,Income ,Androstenes ,Health Expenditures ,business - Abstract
BACKGROUND Abiraterone and enzalutamide are high-cost oral therapies that increasingly are used to treat patients with advanced prostate cancer; these agents carry the potential for significant financial consequences to patients. In the current study, the authors investigated coping and material measures of the financial hardship of these therapies among patients with Medicare Part D coverage. METHODS The authors performed a retrospective cohort study on a 20% sample of Medicare Part D enrollees who underwent treatment with abiraterone or enzalutamide between July 2013 and June 2015. The authors described the variability in adherence rates and out-of-pocket payments among hospital referral regions in the first 6 months of therapy and determined whether adherence and out-of-pocket payments were associated with patient factors and the socioeconomic characteristics of where a patient was treated. RESULTS There were 4153 patients who filled abiraterone or enzalutamide prescriptions through Medicare Part D in 228 hospital referral regions. The mean adherence rate was 75%. The median monthly out-of-pocket payment for abiraterone and enzalutamide was $706 (range, $0-$3505). After multilevel, multivariable adjustment for patient and regional factors, adherence was found to be lower in patients who were older (69% for patients aged ≥85 years vs 76% for patients aged
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- 2020
37. Development of 5D3-DM1: A Novel Anti-Prostate-Specific Membrane Antigen Antibody-Drug Conjugate for PSMA-Positive Prostate Cancer Therapy
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Xin Guo, Shawn E. Lupold, Colin T. Huang, Dmitri Artemov, Venu Raman, Martin G. Pomper, Cyril Bařinka, Sudath Hapuarachchige, and Kathleen L. Gabrielson
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Glutamate Carboxypeptidase II ,Male ,Immunoconjugates ,medicine.drug_class ,medicine.medical_treatment ,Mice, Nude ,Pharmaceutical Science ,02 engineering and technology ,urologic and male genital diseases ,Mertansine ,Monoclonal antibody ,030226 pharmacology & pharmacy ,Article ,Targeted therapy ,Androgen deprivation therapy ,Mice ,03 medical and health sciences ,chemistry.chemical_compound ,Prostate cancer ,0302 clinical medicine ,Cell Line, Tumor ,Nitriles ,Phenylthiohydantoin ,Drug Discovery ,medicine ,Animals ,Humans ,Enzalutamide ,Cellular localization ,Centrosome ,business.industry ,Antibodies, Monoclonal ,Cancer ,Androgen Antagonists ,021001 nanoscience & nanotechnology ,medicine.disease ,Xenograft Model Antitumor Assays ,Tubulin Modulators ,Prostatic Neoplasms, Castration-Resistant ,chemistry ,Antigens, Surface ,Benzamides ,PC-3 Cells ,Cancer research ,Molecular Medicine ,Androstenes ,0210 nano-technology ,business - Abstract
Prostate cancer (PC) is a potentially high-risk disease and the most common cancer in American men. It is a leading cause of cancer-related deaths in men in the US, second only to lung and bronchus cancer. Advanced and metastatic PC is initially treated with androgen deprivation therapy (ADT), but nearly all cases eventually progress to castrate-resistant prostate cancer (CRPC). CRPC is incurable in the metastatic stage but can be slowed by some conventional chemotherapeutics and second-generation ADT, such as enzalutamide and abiraterone. Therefore, novel therapeutic strategies are urgently needed. Prostate-specific membrane antigen (PSMA) is overexpressed in almost all aggressive PCs. PSMA is widely used as a target for PC imaging and drug delivery. Anti-PSMA monoclonal antibodies (mAbs) have been developed as bioligands for diagnostic imaging and targeted PC therapy. However, these mAbs are successfully used in PC imaging and only a few have gone beyond phase-I for targeted therapy. The 5D3 mAb is a novel, high-affinity, and fast-internalizing anti-PSMA antibody. Importantly, 5D3 mAb demonstrates a unique pattern of cellular localization to the centrosome after internalization in PSMA(+) PC3-PIP cells. These characteristics make 5D3 mAb an ideal bioligand to deliver tubulin inhibitors, such as mertansine, to the cell centrosome, leading to mitotic arrest and elimination of dividing PC cells. We have successfully developed a 5D3 mAb- and mertansine (DM1)-based antibody-drug conjugate (ADC) and evaluated it in vitro for binding affinity, internalization, and cytotoxicity. The in vivo therapeutic efficacy of 5D3-DM1 ADC was evaluated in PSMA(+) PC3-PIP and PSMA(–) PC3-Flu mouse models of human PC. This therapeutic study has revealed that this new anti-PSMA ADC can successfully control the growth of PSMA(+) tumors without inducing systemic toxicity.
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- 2020
38. A randomized trial on the effect of oral combined estradiol and drospirenone on glucose and insulin metabolism in healthy menopausal women with a normal oral glucose tolerance test
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Frank Z. Stanczyk, Joris R. Delanghe, Anneloor Dierickx, F. Vandevelde, Herman Depypere, Bruno Lapauw, and L. Ottoy
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Blood Glucose ,medicine.medical_specialty ,Hormone Replacement Therapy ,medicine.medical_treatment ,Administration, Oral ,Placebo ,General Biochemistry, Genetics and Molecular Biology ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Insulin resistance ,Double-Blind Method ,Diabetes mellitus ,Internal medicine ,medicine ,Hyperinsulinemia ,Humans ,Insulin ,Glucose homeostasis ,030212 general & internal medicine ,Mineralocorticoid Receptor Antagonists ,030219 obstetrics & reproductive medicine ,Estradiol ,business.industry ,Obstetrics and Gynecology ,Estrogens ,Drospirenone ,Glucose Tolerance Test ,Middle Aged ,medicine.disease ,Postmenopause ,Drug Combinations ,Glucose ,Fructosamine ,Endocrinology ,chemistry ,Androstenes ,Female ,business ,medicine.drug - Abstract
Background: Menopause is often associated with a central accumulation of body fat. This provokes insulin resistance. The resulting hyperinsulinemia may increase the risk of diabetes, cardiovascular disease and breast cancer. Long-term studies indicate that menopausal hormone therapy (MHT) reduces insulin resistance. To broaden knowledge of the mechanisms behind the influence of MHT on glucose homeostasis we focused on the direct short-term effects of MHT with oral combined estradiol and drospirenone on glucose and insulin metabolism in healthy postmenopausal women. Methods: This randomized, placebo-controlled study recruited 80 healthy postmenopausal women. Women were randomized to treatment with estradiol 1 mg continuously combined with drospirenone 2 mg or placebo for 6-8 weeks. All participants underwent an oral glucose tolerance test (OGTT) before and after the treatment period. Glucose, insulin, fructosamine and C-peptide levels were measured in serum before and 30, 60, 90, 120 and 150 min after a 75-gram oral glucose challenge. Results: After intervention, significantly higher glucose levels at 120 min (p < 0.024) and 150 min (p < 0.030) were observed in the MHT group compared with the placebo group. These glucose levels remained within the normal range. A significantly lower insulin peak serum level (p < 0.040) and a non-significantly smaller area under the curve (AUC) for insulin levels (p = 0.192) was observed in the MHT group at the end of the study period relative to baseline. No significant change in the insulin AUC in the placebo group was observed. There were no significant differences in fructosamine, HOMA-IR and C-peptide levels between the MHT group and the placebo group. Conclusion: This double-blind randomized study (EC/2008/694) indicates that treating healthy, postmenopausal women with 1 mg estradiol continuously combined with 2 mg drospirenone significantly decreases peak insulin levels and increases peak glucose levels during an OGTT compared to placebo. These glucose levels remained within the normal range.
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- 2020
39. YB-1 variant and androgen receptor axis-targeted agents in metastatic castration-resistant prostate cancer patients
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Filipa Carneiro, Rui Medeiros, Sara Coelho, Ana Rita Pinto, Ana Rita Lopes, Maria Joaquina Maurício, Ana Sofia Patrão, Jani Silva, Alina Rosinha, and Ana Afonso
- Subjects
Male ,0301 basic medicine ,Oncology ,medicine.medical_specialty ,Genotype ,Antineoplastic Agents ,Disease-Free Survival ,Cohort Studies ,03 medical and health sciences ,chemistry.chemical_compound ,Prostate cancer ,0302 clinical medicine ,Internal medicine ,Genetics ,medicine ,Humans ,Enzalutamide ,Allele ,Genotyping ,Aged ,Aged, 80 and over ,Pharmacology ,business.industry ,Abiraterone acetate ,Middle Aged ,medicine.disease ,Androgen receptor ,Prostatic Neoplasms, Castration-Resistant ,030104 developmental biology ,chemistry ,Drug Resistance, Neoplasm ,Receptors, Androgen ,Genetic marker ,030220 oncology & carcinogenesis ,Disease Progression ,Molecular Medicine ,Androstenes ,Y-Box-Binding Protein 1 ,business - Abstract
Aim: To evaluate the influence of YB-1 rs10493112 variant as a genetic marker for response to second-generation androgen receptor axis-target agents. Methods: A hospital-based cohort study of 78 patients with metastatic castration-resistant prostate cancer was conducted. Genotyping was performed by TaqMan®allelic discrimination technology. Main results: In abiraterone-treated and high-risk patients, YB-1 rs10493112 AA genotype carriers showed lower progression-free survival than C allele genotype patients (4 vs 17 months; p = 0.009). For carriers of AA genotype, multivariate Cox regression analysis revealed a fivefold increased risk of progression (p = 0.035). Conclusion: The study findings suggest that, for metastatic and castration-resistant prostate cancer patients, this polymorphism might be a putative marker for the clinical outcome.
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- 2020
40. Treatment Patterns and Outcomes in Patients With Metastatic Castration-resistant Prostate Cancer in a Real-world Clinical Practice Setting in the United States
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XiaoLong Jiao, Fred Saad, Kurt Miller, Oliver Sartor, Celestia S. Higano, Daniel J. George, Krishna Tangirala, Ján Kalinovský, Cora N. Sternberg, Bertrand Tombal, UCL - SSS/IREC/CHEX - Pôle de chirgurgie expérimentale et transplantation, and UCL - (SLuc) Service d'urologie
- Subjects
Male ,medicine.medical_specialty ,Electronic health record ,Urology ,Community practice ,Flatiron Health ,030232 urology & nephrology ,Docetaxel ,law.invention ,Database ,03 medical and health sciences ,Prostate cancer ,chemistry.chemical_compound ,0302 clinical medicine ,Randomized controlled trial ,law ,Internal medicine ,Antineoplastic Combined Chemotherapy Protocols ,Nitriles ,Phenylthiohydantoin ,Humans ,Medicine ,Enzalutamide ,Aged ,Retrospective Studies ,Tissue Extracts ,business.industry ,Clinical study design ,Retrospective cohort study ,Prognosis ,medicine.disease ,Survival Rate ,Clinical trial ,Retrospective study ,Prostatic Neoplasms, Castration-Resistant ,Oncology ,chemistry ,Cabazitaxel ,030220 oncology & carcinogenesis ,Benzamides ,Androstenes ,Taxoids ,business ,Follow-Up Studies ,medicine.drug - Abstract
Background Clinical trials have demonstrated the efficacy of several life-prolonging therapies for metastatic castration-resistant prostate cancer (mCRPC); however, real-world data on their use, survival effect, and safety are limited. Using electronic health record data from the Flatiron Health database, we studied real-world treatment patterns and health outcomes in patients with mCRPC. Patients and Methods We conducted a retrospective, non-interventional cohort analysis of electronic health record data of patients with confirmed mCRPC between January 2013 and September 2017. The primary objective was to describe real-world treatment patterns, including treatment type, duration, and sequencing. Secondary objectives included describing patient characteristics and clinical outcomes. Results Of 2559 patients with mCRPC, 1980 (77%) received at least 1 line of life-prolonging therapy (abiraterone, enzalutamide, docetaxel, cabazitaxel, sipuleucel-T, or radium-223). Of patients receiving first-line therapy, 49% received second-line therapy, and of these, 43% received third-line therapy. Abiraterone/prednisone and enzalutamide accounted for 65% of first-line therapies and 54% of second-line therapies. Docetaxel was the most common third-line therapy (24%). Back-to-back use of abiraterone/prednisone and enzalutamide was common. Radium-223 monotherapy use was 2% in the first-line setting, 3% in the second-line setting, and 8% in the third-line setting. The median overall survival was longer in patients who received life-prolonging therapies (23.7 months; 95% confidence interval: 22.3-25.1 months) than in those who did not (10.1 months; 95% confidence interval: 9.1-11.5 months). Conclusion These real-world insights on over 2500 patients with mCRPC supplement findings from randomized controlled trials and may help to inform clinical trial design, treatment guidelines, and clinical decision-making.
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- 2020
41. Adding carboplatin to chemotherapy regimens for metastatic castrate‐resistant prostate cancer in postsecond generation hormone therapy setting: Impact on treatment response and survival outcomes
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Vidhu B. Joshi, Paras Shah, Mohamed E. Ahmed, Eugene Kwon, Jamal Alamiri, Rimki Haloi, Giovanni Motterle, Jack R. Andrews, Julianna Higa, R. Jeffrey Karnes, and Manaf Alom
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Male ,0301 basic medicine ,Oncology ,medicine.medical_specialty ,Urology ,medicine.medical_treatment ,Docetaxel ,Carboplatin ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Positron Emission Tomography Computed Tomography ,Internal medicine ,Antineoplastic Combined Chemotherapy Protocols ,Nitriles ,Phenylthiohydantoin ,medicine ,Humans ,Enzalutamide ,Treatment Failure ,Neoplasm Metastasis ,Aged ,Retrospective Studies ,Chemotherapy ,business.industry ,Hazard ratio ,Chemotherapy regimen ,Survival Rate ,Prostatic Neoplasms, Castration-Resistant ,030104 developmental biology ,chemistry ,Cabazitaxel ,030220 oncology & carcinogenesis ,Benzamides ,Disease Progression ,Androstenes ,Taxoids ,Hormone therapy ,business ,medicine.drug - Abstract
Background The clinical course in metastatic castrate-resistant prostate cancer (mCRPC) can be complicated when patients have disease progression after prior treatment with second generation hormone therapy (second HT), such as enzalutamide or abiraterone. Currently, limited data exist regarding the optimal choice of chemotherapy for mCRPC after failing second generation hormone therapy. We sought to evaluate three common chemotherapy regimens in this setting. Methods We retrospectively identified 150 mCRPC patients with disease progression on enzalutamide or abiraterone. Of these 150 patients, 92 patients were chemo-naive while 58 patients had previously received docetaxel chemotherapy before being started on second HT. After failing second HT, 90 patients were assigned for docetaxel-alone (group A), 33 patients received carboplatin plus docetaxel (group B), while 27 patients received cabazitaxel-alone (Group C). A favorable response was defined by more than or equal to 50% reduction in prostate-specific antigen from the baseline level after a complete course of chemotherapy. Survival outcomes were assessed for 30-month overall survival. Results Patients in group (B) were 2.6 times as likely to have a favorable response compared to patients in group (A) (OR = 2.625, 95%CI: 1.15-5.99) and almost three times compared to patients in group (C) (OR = 2.975, 95%CI: 1.04-8.54) (P = .0442). 30-month overall survival was 70.7%, 38.9% and 30.3% for group (B), (A), and (C), respectively (P = .008). We report a Hazard Ratio of 3.1 (95% CI, 1.31-7.35; P = .0037) between patients in group (A) versus those in group (B) and a Hazard Ratio of 4.18 (95% CI, 1.58-11.06; P = .0037) between patients in group (C) compared to those in group (B) CONCLUSION: This data demonstrates improved response and overall survival in treatment-refractory mCRPC with a chemotherapy regimen of docetaxel plus carboplatin when compared to docetaxel alone or cabazitaxel alone. Further investigations are required.
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- 2020
42. Identifying Prostate Surface Antigen Patterns of Change in Patients with Metastatic Hormone Sensitive Prostate Cancer Treated with Abiraterone and Prednisone
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Hong Li, Iris Yeong Fung Sheng, Timothy D. Gilligan, Ruby Gupta, Pedro C. Barata, Moshe Chaim Ornstein, Jaleh Fallah, Allison Martin, Jorge A Garcia, Brian I. Rini, and Kimberly D Allman
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Male ,0301 basic medicine ,Cancer Research ,medicine.medical_specialty ,Urology ,urologic and male genital diseases ,Serology ,Androgen deprivation therapy ,03 medical and health sciences ,chemistry.chemical_compound ,Prostate cancer ,0302 clinical medicine ,Interquartile range ,Prednisone ,Prostate ,Antineoplastic Combined Chemotherapy Protocols ,medicine ,Humans ,Pharmacology (medical) ,Survival analysis ,Aged ,business.industry ,Abiraterone acetate ,medicine.disease ,Survival Analysis ,Prostatic Neoplasms, Castration-Resistant ,Treatment Outcome ,030104 developmental biology ,medicine.anatomical_structure ,Oncology ,chemistry ,030220 oncology & carcinogenesis ,Antigens, Surface ,Androstenes ,business ,medicine.drug - Abstract
Despite treatment with abiraterone acetate and prednisone (AA/P), most patients with metastatic hormone sensitive prostate cancer (mHSPC) will develop castration-resistant disease (metastatic castration-resistant prostate cancer [mCRPC]). The early identification of who will progress on AA/P is limited. This study investigates the role of prostate surface antigen (PSA) kinetics as a predictor of progression in mHSPC patients treated with AA/P. All patients with mHSPC who initiated androgen deprivation therapy (ADT) and AA/P from June 2017 to February 2019 at the Cleveland Clinic were eligible. PSA-mCRPC was defined as a PSA rise at two consecutive time points. Patients were followed until first mCRPC or last contact after AA/P. Patterns of PSA change were evaluated using a longitudinal mixed model at time 0, 3, 6, 9, and 12 months from AA/P initiation. The association between PSA profile at 3 months and PSA-mCRPC was examined using survival analysis. Radiographic progression (Rad-mCRPC) was also analyzed. A total of 130 men with follow-up were included. The median (interquartile range [IQR]) follow-up time was 15.3 (10.5, 22.5) months. Eighty-two percent were Caucasian (median age 68.5 years); participants had a median (IQR) PSA of 16.8 (5.3, 48.0) ng/mL. Half of the patients had de novo disease, and 46.2% had high-risk disease (61% had a Gleason score ≥ 8, 16% had visceral disease, and 54% had three or more bony lesions). The greatest PSA percentage reduction from baseline after AA/P initiation occurred at the first 3 months (median 98.3%). The reduction at 6–12 months from baseline was small (99.7–100%). Patients without PSA-mCRPC had a significantly greater 3-month reduction of PSA values compared to patients who developed PSA-mCRPC (p interaction = 0.0002). 50.8% of patients were able to achieve a non-detectable PSA (median 13.1 months). PSA-mCRPC (n = 20) was observed from 4 to 24 months after AA/P, with the majority of events occurring within the first 12 months. Patients with PSA
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- 2020
43. Comparing the clinical efficacy and safety of abiraterone and enzalutamide in metastatic castration-resistant prostate cancer: A systematic review and meta-analysis
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Xiaopeng Hu, Wei Wang, Shihui Wang, Xiaojia Yu, Xin Wang, Lihong Liu, Xiaodong Zhang, and Hui Yang
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Male ,Oncology ,medicine.medical_specialty ,Castration resistant ,Cohort Studies ,03 medical and health sciences ,Prostate cancer ,chemistry.chemical_compound ,0302 clinical medicine ,Internal medicine ,Nitriles ,Phenylthiohydantoin ,Humans ,Medicine ,Enzalutamide ,Pharmacology (medical) ,In patient ,030212 general & internal medicine ,Clinical efficacy ,Beneficial effects ,Aged ,business.industry ,Prostate-Specific Antigen ,medicine.disease ,Progression-Free Survival ,Prostatic Neoplasms, Castration-Resistant ,Abiraterone ,Treatment Outcome ,chemistry ,030220 oncology & carcinogenesis ,Meta-analysis ,Benzamides ,Androstenes ,business - Abstract
Background Two new drugs, abiraterone and enzalutamide, had recently shown beneficial effects on survival in patients with metastatic castration-resistant prostate cancer. We systematically reviewed the efficacy and safety of abiraterone and enzalutamide in metastatic castration-resistant prostate cancer in real-world practice. Methods A search from PubMed, Web of Science, Cochrane, Embase was conducted up to 6 March 2019. Available articles from conferences were searched. The endpoint was prostate-specific antigen response, overall survival, progression-free survival, number of patients with any adverse event. Results Fourteen cohort studies involving 3469 participants were included. Pooled result showed that prostate-specific antigen response was higher for patients receiving enzalutamide than abiraterone (790 patients, odds ratio (OR) 0.47, 95% confidence interval (CI) 0.29–0.77, P = 0.003, I2=59%). Enzalutamide was significantly associated with increased adverse events rate in comparison with abiraterone (730 patients, OR 0.35, 95%CI 0.13–0.92, P = 0.03, I2=65%). There was no statistical difference between abiraterone and enzalutamide with respect to perceived cognitive impairments (1856 patients, OR 0.90, 95%CI 0.29–2.76, P = 0.85, I2=5%). Enzalutamide was significantly associated with increased fatigue risk in comparison with abiraterone (2477 patients, OR 0.46, 95%CI 0.34–0.63, P<0.00001, I2=0%). Conclusions Our results demonstrated that enzalutamide was more efficacious than abiraterone for patients with metastatic castration-resistant prostate cancer, but was associated with a significantly elevated risk of side effects, particularly fatigue.
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- 2020
44. Blood platelet volume predicts treatment-specific outcomes of metastatic castration-resistant prostate cancer
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Wataru Fukuokaya, Kojiro Tashiro, Yusuke Koike, Hiroshi Sasaki, Shunsuke Tsuzuki, Shoji Kimura, Kenta Miki, Fumihiko Urabe, Shin Egawa, and Takahiro Kimura
- Subjects
Male ,0301 basic medicine ,Oncology ,medicine.medical_specialty ,Erythrocytes ,Docetaxel ,Lower risk ,03 medical and health sciences ,chemistry.chemical_compound ,Prostate cancer ,0302 clinical medicine ,Internal medicine ,Nitriles ,Phenylthiohydantoin ,Biomarkers, Tumor ,medicine ,Humans ,Enzalutamide ,Mean platelet volume ,Aged ,Proportional Hazards Models ,Retrospective Studies ,Platelet Count ,business.industry ,Proportional hazards model ,Hazard ratio ,Abiraterone acetate ,Hematology ,General Medicine ,Prostate-Specific Antigen ,Prognosis ,medicine.disease ,Prostatic Neoplasms, Castration-Resistant ,Treatment Outcome ,030104 developmental biology ,chemistry ,Receptors, Androgen ,030220 oncology & carcinogenesis ,Benzamides ,Androstenes ,Surgery ,business ,Mean Platelet Volume ,medicine.drug - Abstract
In the present guidelines for the management of metastatic castration-resistant prostate cancer (mCRPC), it is unclear who benefits most from androgen receptor axis-targeted agents (ARATs) or docetaxel as the first-line treatment. We conducted a retrospective study to explore new treatment-specific biomarkers in mCRPC. A total of 211 patients with mCRPC who received either ARAT or docetaxel as first-line treatment were included. Patients were compared for radiographic progression and prostate-specific antigen (PSA) progression. Multivariable Cox regression models were used to assess the association between pretreatment biomarkers and risk of events. The statistical interaction between biomarkers and clinical outcomes was also evaluated. Of all analyzed biomarkers, multivariable Cox regression models identified MPV [≤ median (9.7 fL)] as an independent prognostic factor of radiographic progression [hazard ratio (HR), 2.35; 95% confidence interval (CI), 1.15–4.80; P = 0.019] and PSA progression (HR, 1.96; 95% CI, 1.01–3.95; P = 0.048) in patients treated with ARAT, whereas such associations were not observed in those treated with docetaxel. Interaction analyses showed that those initially treated with docetaxel have lower risk of radiographic progression (HR, 0.33; 95% CI, 0.13–0.79; P = 0.014) and PSA progression (HR, 0.48; 95% CI, 0.23–0.98; P = 0.044) than ARAT when MPV was small. The present study identified pretreatment MPV as a significant treatment-specific prognostic factor of PSA and radiographic progression in patients with mCRPC who received first-line treatment. Furthermore, our results suggested that those with small MPV may better be treated initially with docetaxel than ARAT.
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- 2020
45. Pharmacotherapeutic strategies for castrate-resistant prostate cancer
- Author
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Athanasios Papatsoris, Despoina Sryropoulou, Mohamed Abou Chakra, Mohamad Moussa, and Athanasios Dellis
- Subjects
Male ,Oncology ,Radium-223 ,medicine.medical_specialty ,Abiraterone Acetate ,Castrate-resistant prostate cancer ,Docetaxel ,Disease ,urologic and male genital diseases ,Disease-Free Survival ,03 medical and health sciences ,chemistry.chemical_compound ,Prostate cancer ,0302 clinical medicine ,Internal medicine ,Antineoplastic Combined Chemotherapy Protocols ,Nitriles ,Phenylthiohydantoin ,medicine ,Humans ,Enzalutamide ,Pharmacology (medical) ,Pharmacology ,Clinical Trials as Topic ,Tissue Extracts ,business.industry ,Apalutamide ,Abiraterone acetate ,General Medicine ,medicine.disease ,Progression-Free Survival ,Prostatic Neoplasms, Castration-Resistant ,Sipuleucel-T ,chemistry ,Drug Resistance, Neoplasm ,030220 oncology & carcinogenesis ,Benzamides ,Prednisone ,Androstenes ,Taxoids ,Immunotherapy ,business ,030217 neurology & neurosurgery ,Radium ,medicine.drug - Abstract
Metastatic castration-resistant prostate cancer (CRPC) is a potentially symptomatic disease with an eventual lethal outcome. Novel pharmaceutical agents are continuously studied with encouraging results in CRPC.In this perspective, the authors present established and promising pharmacotherapeutic strategies for the management of CRPC; both with and without metastases. Apart from the different treatment strategies, the authors present the relevant sequence of treatment through disease progression.Usually, docetaxel should be considered the first line treatment in mCRPC. Abiraterone acetate (AA) plus prednisone or enzalutamide (ENZ) could be alternative treatments in chemotherapy naïve patients. Sipuleucel-T has been approved for the treatment of asymptomatic or minimally symptomatic mCRPC. Ra-223 has been approved for patients with mCRPC with symptomatic bone metastases (not visceral metastases). Cabazitaxel has been approved as the second line treatment to docetaxel in mCRPC. No differences in the overall survival has been observed between sequences starting with docetaxel versus AA/ENZ. Between AA-to-ENZ and ENZ-to-AA sequence, the AA-to-ENZ sequence appeared to be more favorable than the ENZ-to-AA regarding progression-free survival but not overall survival. Carbazitaxel seemed to retain its activity regardless of the treatment sequence. Of note, ENZ and apalutamide have been approved in non-metastatic CRPC.
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- 2020
46. Concurrent or layered treatment with radium-223 and enzalutamide or abiraterone/prednisone: real-world clinical outcomes in patients with metastatic castration-resistant prostate cancer
- Author
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Oliver Sartor, XiaoLong Jiao, Celestia S. Higano, Kurt Miller, Krishna Tangirala, Daniel J. George, Neal D. Shore, J. Kalinovsky, Bertrand Tombal, Cora N. Sternberg, Fred Saad, UCL - SSS/IREC/CHEX - Pôle de chirgurgie expérimentale et transplantation, and UCL - (SLuc) Service d'urologie
- Subjects
Oncology ,Male ,Cancer Research ,Cancer therapy ,Zoledronic Acid ,chemistry.chemical_compound ,Prostate cancer ,0302 clinical medicine ,Prednisone ,Antineoplastic Combined Chemotherapy Protocols ,Multicenter Studies as Topic ,030212 general & internal medicine ,Neoplasm Metastasis ,Randomized Controlled Trials as Topic ,Aged, 80 and over ,Bone Density Conservation Agents ,Chemoradiotherapy ,Middle Aged ,Survival Rate ,Prostatic Neoplasms, Castration-Resistant ,Treatment Outcome ,Outcomes research ,030220 oncology & carcinogenesis ,Benzamides ,Prednisolone ,Androstenes ,Denosumab ,medicine.drug ,Radium ,Radium-223 ,Adult ,medicine.medical_specialty ,Urology ,Bone Neoplasms ,Article ,03 medical and health sciences ,Internal medicine ,Nitriles ,Phenylthiohydantoin ,medicine ,Enzalutamide ,Humans ,Aged ,Retrospective Studies ,business.industry ,Retrospective cohort study ,medicine.disease ,Abiraterone ,chemistry ,Clinical Trials, Phase III as Topic ,Concomitant ,business - Abstract
Background In this study, we evaluated real-world data on radium-223 plus abiraterone/prednisone or enzalutamide. Previously, the ERA 223 trial (NCT02043678) demonstrated increased fracture risk with concurrent treatment with radium-223 and abiraterone plus prednisone/prednisolone in patients with metastatic castration-resistant prostate cancer (mCRPC). Methods We used the Flatiron Health database to perform a retrospective study of patients with mCRPC treated with radium-223. Treatment with radium-223 plus abiraterone/prednisone or enzalutamide was defined as concurrent if both drugs started within 30 days of one another, or layered when the second drug started ≥30 days after the first. The index date was defined as the day of the first radium-223 dose. Outcome measures included symptomatic skeletal events (SSEs), overall survival (OS), and patterns of treatments received. Results Of the 625 patients treated with radium-223, 22% received it together with abiraterone/prednisone and 27% with enzalutamide. When these agents were combined, they were often initiated in a layered fashion (73% layered, 23% concurrent). Prior or concomitant bone health agents (BHAs) were received by 67% and 55% of patients, respectively. Median follow-up was 9 months. Overall, incidence rates for SSEs and pathologic fractures were 0.35 and 0.11 patients per person-year, respectively. Median OS from mCRPC diagnosis was 28.1 months. Conclusions In this real-world setting, combination treatments with radium-223 and abiraterone/prednisone or enzalutamide were common. These agents were more commonly given in a layered than a concurrent fashion. Incidence rates for SSEs were reduced when BHAs were used; however, BHAs were underutilized.
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- 2020
47. Abiraterone acetate treatment lowers 11-oxygenated androgens
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Nima Sharifi, Richard J. Auchus, Mohammed Alyamani, Patrick O’Day, and Connor Wright
- Subjects
Adult ,Male ,medicine.medical_specialty ,Endocrinology, Diabetes and Metabolism ,Abiraterone Acetate ,030209 endocrinology & metabolism ,Context (language use) ,urologic and male genital diseases ,Article ,03 medical and health sciences ,Prostate cancer ,chemistry.chemical_compound ,0302 clinical medicine ,Endocrinology ,Tandem Mass Spectrometry ,Internal medicine ,medicine ,Cytochrome P-450 Enzyme Inhibitors ,Humans ,Testosterone ,Androstenedione ,Adrenal Hyperplasia, Congenital ,business.industry ,Abiraterone acetate ,Prostatic Neoplasms ,General Medicine ,Prodrug ,medicine.disease ,Castration ,chemistry ,CYP17A1 ,030220 oncology & carcinogenesis ,Androgens ,Prednisone ,Androstenes ,Drug Therapy, Combination ,business ,Chromatography, Liquid - Abstract
Context The human adrenal is the dominant source of androgens in castration-resistant prostate cancer (CRPC) and classic 21-hydroxylase deficiency (21OHD). Abiraterone, derived from the prodrug abiraterone acetate (AA), inhibits the activity of cytochrome P450 17-hydroxylase/17,20-lyase (CYP17A1), the enzyme required for all androgen biosynthesis. AA treatment effectively lowers testosterone and androstenedione in 21OHD and CRPC patients. The 11-oxygenated androgens are major adrenal-derived androgens, yet little is known regarding the effects of AA administration on 11-oxygenated androgens. Objective To test the hypothesis that AA therapy decreases 11-oxygenated androgens. Design Samples were obtained from 21OHD or CRPC participants in AA or AA plus prednisone (AAP)-treatment studies, respectively. Methods We employed liquid chromatography-tandem mass spectrometry (LC-MS/MS) to measure the 11-oxygenated androgens, 11β-hydroxyandrostenedione, 11-ketoandrostenedione, 11β-hydroxytestosterone, and 11-ketotestosterone, in plasma or serum samples from six 21OHD and six CRPC patients before and after treatment with AA or AAP, respectively. Results In CRPC patients, administration of AAP (1000 mg/day AA with prednisone and medical castration) lowered all four 11-oxygenated androgens to below the lower limits of quantitation ( Conclusions We conclude that AA and AAP therapies markedly reduce the production of the adrenal-derived 11-oxygenated androgens, both in patients with high (21OHD) or normal (CRPC) 11-oxygenated androgens at baseline, respectively. Reduction of 11-oxygenated androgens is an important aspect of AA and AAP pharmacology.
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- 2020
48. Revealing the prognostic landscape of neutrophil-to-lymphocyte ratio and platelet-to-lymphocyte ratio in metastatic castration-resistant prostate cancer patients treated with abiraterone or enzalutamide: a meta-analysis
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Guolong Liao, Jun Pang, Tongyu Tong, Yupeng Guan, Haiyun Xiong, and Yu-Peng Feng
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Blood Platelets ,Male ,Oncology ,Cancer Research ,medicine.medical_specialty ,Neutrophils ,Urology ,030232 urology & nephrology ,Cochrane Library ,law.invention ,03 medical and health sciences ,chemistry.chemical_compound ,Prostate cancer ,0302 clinical medicine ,Randomized controlled trial ,law ,Internal medicine ,Antineoplastic Combined Chemotherapy Protocols ,Nitriles ,Phenylthiohydantoin ,Biomarkers, Tumor ,medicine ,Humans ,Enzalutamide ,Lymphocytes ,Neutrophil to lymphocyte ratio ,business.industry ,Hazard ratio ,Prognosis ,medicine.disease ,Prostatic Neoplasms, Castration-Resistant ,chemistry ,030220 oncology & carcinogenesis ,Meta-analysis ,Benzamides ,Androstenes ,business ,Cohort study - Abstract
The neutrophil-to-lymphocyte ratio (NLR) and the platelet-to-lymphocyte ratio (PLR), as markers of systematic inflammation response, have been reported to be indicators in metastatic castration-resistant prostate cancer (mCRPC), whereas their prognostic values remain conflict. This study was to assess the prognostic value of NLR and PLR in mCRPC patients and to assess the response of abiraterone or enzalutamide through using NLR and PLR. Databases searching was conducted in the PubMed, EMBASE, Google Scholar, and the Cochrane Library for relevant published literature up to October 2019. Data extraction and quality evaluation were performed on the eligible studies. STATA 14.0 software was used to pooled hazard ratios (HRs) and their 95% confidence intervals (CIs) for overall survival (OS) and progression-free survival (PFS). A total of 3144 mCRPC patients were enrolled from 15 cohort studies in this meta-analysis. The pooled results demonstrated that elevated NLR had a significant association with inferior OS in mCRPC patients treated with abiraterone (HR = 1.63, 95% CI: 1.43–1.85, P
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- 2020
49. Application of the ASCO Value Framework and ESMO Magnitude of Clinical Benefit Scale to Assess the Value of Abiraterone and Enzalutamide in Advanced Prostate Cancer
- Author
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Louis Everest, Sarah E. Wong, Di Maria Jiang, Srikala S. Sridhar, Kelvin K. W. Chan, and Ronak Saluja
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Male ,Oncology ,medicine.medical_specialty ,Medical Oncology ,03 medical and health sciences ,chemistry.chemical_compound ,Prostate cancer ,0302 clinical medicine ,Internal medicine ,Nitriles ,Phenylthiohydantoin ,medicine ,Humans ,Enzalutamide ,030212 general & internal medicine ,Cost implications ,Oncology (nursing) ,business.industry ,Health Policy ,Prostatic Neoplasms ,medicine.disease ,Abiraterone ,chemistry ,030220 oncology & carcinogenesis ,Benzamides ,Androstenes ,business ,Value framework - Abstract
PURPOSE: As novel hormonal therapies, such as abiraterone and enzalutamide, move into earlier stages of treatment of advanced prostate cancer, there are significant cost implications. We used the ASCO Value Framework (AVF) and European Society of Medical Oncology (ESMO) Magnitude of Clinical Benefit Scale (MCBS) to quantify and compare the incremental clinical benefit and costs of these agents in the metastatic castration-resistant prostate cancer (mCRPC) and metastatic castration-sensitive prostate cancer (mCSPC) settings. METHODS: We searched PubMed for randomized phase III trials of abiraterone and enzalutamide in mCRPC and mCSPC. Incremental clinical benefit was quantified using the AVF and ESMO-MCBS by 2 independent assessors. Incremental drug costs were calculated using average wholesale prices (AWPs) from the RED BOOK Online. RESULTS: In mCRPC, 2 abiraterone trials (COU-AA-301 and COU-AA-302) and 2 enzalutamide trials (AFFIRM and PREVAIL) met search criteria. AVF scores ranged from 46.3 to 66.6, suggesting clinical benefit; ESMO-MCBS scores ranged from 3 to 5, with lower clinical benefit in the mCRPC predocetaxel setting. The overall incremental AWP ranged from $83,460.94 to $205,128.85. In mCSPC, 4 trials met criteria (LATITUDE, STAMPEDE, ENZAMET, and ARCHES; AVF scores were 79.8, 33.3, 59, and 17, respectively). All of the studies showed benefit except ARCHES. By ESMO-MCBS, both LATITUDE and STAMPEDE showed benefit (score for 4 for both studies); ENZAMET and ARCHES were not evaluable. The overall cost of treatment was significantly higher in the mCSPC setting. CONCLUSION: The AVF and ESMO-MCBS frameworks generated slightly different results but suggested that abiraterone and enzalutamide show clinical benefit in both mCRPC and mCSPC but trended to lower clinical benefit and increased costs in earlier disease stages. Further refinement of the AVF and ESMO-MCBS is needed to facilitate their use and their ability to inform clinical practice in a rapidly changing treatment landscape.
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- 2020
50. Pregnenolonyl-α-glucoside exhibits marked anti-cancer and CYP17A1 enzymatic inhibitory activities
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Tung-Kung Wu, Jason Wen Jay Lyu, Chin-Yuan Chang, Chia Tse Tsai, Feng-Pai Chou, Wen Chen Hsu, Ya Sheng Chiou, Wei Ting Chen, and Sheng Cih Huang
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Glycosylation ,Antineoplastic Agents ,Catalysis ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Glucosides ,Glucoside ,Catalytic Domain ,Cell Line, Tumor ,Materials Chemistry ,medicine ,Cytochrome P-450 Enzyme Inhibitors ,Humans ,Cytotoxic T cell ,030304 developmental biology ,chemistry.chemical_classification ,0303 health sciences ,Bacteria ,biology ,Metals and Alloys ,Glycoside ,Active site ,General Chemistry ,In vitro ,Surfaces, Coatings and Films ,Electronic, Optical and Magnetic Materials ,Molecular Docking Simulation ,HEK293 Cells ,Enzyme ,chemistry ,Biochemistry ,Docking (molecular) ,Pregnenolone ,030220 oncology & carcinogenesis ,Ceramics and Composites ,biology.protein ,Androstenes ,Protein Binding ,medicine.drug - Abstract
We report here that pregnenolonyl-α-glucoside (2), a steryl glycoside synthesized directly from pregnenolone and glucose via a consecutive multienzyme-catalyzed process, exhibits marked dose-dependent cytotoxic activity against HT29, AGS, and ES-2 cells with IC50 values of 23.5 to 50.9 μM. An in vitro CYP17A1 binding pattern assay and protein-ligand docking model support that 2, like abiraterone, binds in the active site heme iron pocket of CYP17A1.
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- 2020
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