Assuntos
Doença Hepática Induzida por Substâncias e Drogas/complicações , Nefropatias/etiologia , Congêneres da Testosterona/efeitos adversos , Adulto , Androstenóis/efeitos adversos , Doença Hepática Induzida por Substâncias e Drogas/etiologia , Exercício Físico , Hemodiafiltração , Humanos , Hiperbilirrubinemia/induzido quimicamente , Icterícia Obstrutiva/induzido quimicamente , Icterícia Obstrutiva/complicações , Nefropatias/terapia , Masculino , Pró-Fármacos/efeitos adversos , Diálise RenalRESUMO
BACKGROUND: Supplement adulteration with anabolic-androgenic steroids (AAS) has been reported and AAS-associated drug-induced liver injury is clinically variable. OBJECTIVES: We present two cases of AAS-associated drug-induced liver injury in deployed service members, including the first report of clinical hepatotoxicity with desoxymethyltestosterone. We highlight variable hepatotoxicity patterns of AAS, raise concern with inaccurate supplement labeling and identify educational resources. METHODS: The first case presents with cholestatic jaundice following 10 weeks of prohormone use. Hepatobiliary imaging was unrevealing. Viral, autoimmune, and metabolic etiologies were excluded. Bilirubin normalized by 8 weeks after stopping the supplement. The second case presents with asymptomatic hepatocellular toxicity and marked dyslipidemia identified on service-related physical following 21 days of prohormone use. Aspartate aminotransferase and alanine aminotransferase normalized 4 weeks after supplement cessation; high-density lipoprotein and low-density lipoprotein returned to baseline at 8 weeks. Each supplement was volunteered for analytic testing. RESULTS: Supplement label contents did not match gas chromatography/mass spectrometry analysis; 3 of 4 supplements contained federally regulated AAS. CONCLUSIONS: AAS hepatotoxicity is clinically variable and dyslipidemia may be an important clinical indicator. False labeling introduces clinical risk and threatens mission readiness. Educational resources are available to facilitate information sharing. Supplement analysis informs of clinical risk of specific supplements and facilitates shared clinical decision-making.
Assuntos
Androstenóis/efeitos adversos , Doença Hepática Induzida por Substâncias e Drogas/etiologia , Adulto , Androstenóis/uso terapêutico , Androstenóis/toxicidade , Doença Hepática Induzida por Substâncias e Drogas/complicações , Dislipidemias/etiologia , Fadiga/etiologia , Humanos , Icterícia/etiologia , Lipoproteínas HDL/análise , Lipoproteínas HDL/sangue , Lipoproteínas LDL/análise , Lipoproteínas LDL/sangue , Masculino , Militares , Prurido/etiologiaRESUMO
BACKGROUND: With the introduction of oral chemotherapy, the paradigm for cancer treatment is shifting. Use of oral chemotherapy agents offers a non-invasive option for patients with metastatic castrate-resistant prostate cancer. However, these medications are not without challenges including strict adherence for optimal effects, novel toxicity profiles, frequent lab parameter monitoring, high cost, and proper handling and disposal methods. Pharmacists are positioned to play a key role in providing patients with the education required to assure an optimal treatment course is carried out. METHODS: Two cohorts of patients receiving abiraterone, bicalutamide, or enzalutamide for metastatic castrate-resistant prostate cancer seen in our outpatient cancer center 21 months before and 24 months after the implementation of a pharmacist-led oral chemotherapy-monitoring program in December of 2012 were retrospectively compared. Patients were evaluated for number of interventions, adherence to lab parameter monitoring, and overall time on each therapy. RESULTS: Of the 64 patients identified, 31 patients fulfilled inclusion criteria. A significant increase in the average number of interventions per patient (6.9 vs. 2.6; P = 0.004) and adherence to lab parameter monitoring (10 vs. 3; P = 0.04) in the post-program implementation cohort was found. However, no significant difference in overall time on therapy (10.3 vs. 8.1; P = 0.341) between the two groups was observed. CONCLUSION: These results suggest a potential opportunity exists to maximize oral chemotherapy treatment outcomes with the addition of a formalized monitoring program directed by an oncology pharmacist.
Assuntos
Antineoplásicos/administração & dosagem , Monitoramento de Medicamentos/métodos , Farmacêuticos , Papel Profissional , Neoplasias de Próstata Resistentes à Castração/tratamento farmacológico , Administração Oral , Adulto , Idoso , Idoso de 80 Anos ou mais , Androstenos/administração & dosagem , Androstenos/efeitos adversos , Androstenóis/administração & dosagem , Androstenóis/efeitos adversos , Antineoplásicos/efeitos adversos , Benzamidas , Estudos de Coortes , Humanos , Masculino , Pessoa de Meia-Idade , Nitrilas , Feniltioidantoína/administração & dosagem , Feniltioidantoína/efeitos adversos , Feniltioidantoína/análogos & derivados , Neoplasias de Próstata Resistentes à Castração/diagnóstico , Estudos Retrospectivos , Resultado do TratamentoRESUMO
Abiraterone acetate(AA)has been approved in more than 80 countries for the treatment of patients with metastatic castration-resistant prostate cancer(mCRPC). In July 2013, a marketing approval application for AA was submitted to the Japanese Ministry of Health, Labour, and Welfare. AA is a selective inhibitor of CYP17A1, a crucial enzyme for androgen biosynthesis. AA exerts its anti-tumor activity by directly inhibiting androgen production at all three sources, i. e., the testes, adrenal glands, and tumor itself. Data from international phase III studies and phase I and II studies in Japan have indicated that AA improves the overall survival and quality of life(QoL)of patients with mCRPC. Herein, we have summarized the development of AA and the results of important international and local clinical trials in Japan. In addition, the effect of food on AA bioavailability, concomitant steroid use, and liver function test abnormalities have been discussed regarding the appropriate use of AA.
Assuntos
Androstadienos/uso terapêutico , Androstenóis/uso terapêutico , Ensaios Clínicos como Assunto , Inibidores Enzimáticos/uso terapêutico , Neoplasias de Próstata Resistentes à Castração/tratamento farmacológico , Esteroide 17-alfa-Hidroxilase/antagonistas & inibidores , Acetato de Abiraterona , Androstadienos/efeitos adversos , Androstenos , Androstenóis/efeitos adversos , Doença Hepática Induzida por Substâncias e Drogas , Inibidores Enzimáticos/efeitos adversos , Humanos , Masculino , Neoplasias de Próstata Resistentes à Castração/enzimologiaRESUMO
This position paper is intended to help to structure and to standardize therapy monitoring in patients with metastatic castration-resistant prostate cancer (mCRPC). With the treatment options available today, patients with metastatic disease can often maintain good quality of life and stable disease for several years. It is crucial that once a therapy becomes insufficiently effective that it be replaced in a timely manner by a new treatment option. From a prognostic point of view, it is important that patients receive as many as possible and in the ideal case all currently available treatment options.
Assuntos
Antineoplásicos/uso terapêutico , Neoplasias de Próstata Resistentes à Castração/tratamento farmacológico , Androstenos , Androstenóis/efeitos adversos , Androstenóis/uso terapêutico , Antineoplásicos/efeitos adversos , Benzamidas , Progressão da Doença , Docetaxel , Resistencia a Medicamentos Antineoplásicos , Humanos , Masculino , Estadiamento de Neoplasias , Nitrilas , Feniltioidantoína/efeitos adversos , Feniltioidantoína/análogos & derivados , Feniltioidantoína/uso terapêutico , Prognóstico , Neoplasias de Próstata Resistentes à Castração/patologia , Taxoides/efeitos adversos , Taxoides/uso terapêuticoRESUMO
Suppression of gonadal testosterone synthesis represents the standard first line therapy for treatment of metastatic prostate cancer. However, in the majority of patients who develop castration-resistant prostate cancer (CRPC), it is possible to detect persistent activation of the androgen receptor (AR) through androgens produced in the adrenal gland or within the tumor itself. Abiraterone acetate was developed as an irreversible inhibitor of the dual functional cytochrome P450 enzyme CYP17 with activity as a 17α-hydroxylase and 17,20-lyase. CYP17 is necessary for production of nongonadal androgens from cholesterol. Regulatory approval of abiraterone in 2011, based on a phase III trial showing a significant improvement in overall survival (OS) with abiraterone and prednisone versus prednisone, represented proof of principle that targeting AR is essential for improving outcomes in men with CRPC. Inhibition of 17α-hydroxylase by abiraterone results in accumulation of upstream mineralocorticoids due to loss of cortisol-mediated suppression of pituitary adrenocorticotropic hormone (ACTH), providing a rationale for development of CYP17 inhibitors with increased specificity for 17,20-lyase (orteronel, galeterone and VT-464) that can potentially be administered without exogenous corticosteroids. In this article, we review the development of abiraterone and other CYP17 inhibitors; recent studies with abiraterone that inform our understanding of clinical parameters such as drug effects on quality-of-life, potential early predictors of response, and optimal sequencing of abiraterone with respect to other agents; and results of translational studies providing insights into resistance mechanisms to CYP17 inhibitors leading to clinical trials with drug combinations designed to prolong abiraterone benefit or restore abiraterone activity.
Assuntos
Antagonistas de Androgênios/uso terapêutico , Neoplasias de Próstata Resistentes à Castração/tratamento farmacológico , Antagonistas de Androgênios/efeitos adversos , Androstadienos/uso terapêutico , Androstenos , Androstenóis/efeitos adversos , Androstenóis/uso terapêutico , Benzimidazóis/uso terapêutico , Composição Corporal/efeitos dos fármacos , Neoplasias Ósseas/tratamento farmacológico , Neoplasias Ósseas/secundário , Sistema Cardiovascular/efeitos dos fármacos , Ensaios Clínicos como Assunto , Resistencia a Medicamentos Antineoplásicos , Inibidores Enzimáticos/efeitos adversos , Inibidores Enzimáticos/uso terapêutico , Humanos , Imidazóis/uso terapêutico , Masculino , Mineralocorticoides/metabolismo , Naftalenos/uso terapêutico , Células Neoplásicas Circulantes/efeitos dos fármacos , Neoplasias de Próstata Resistentes à Castração/metabolismo , Neoplasias de Próstata Resistentes à Castração/secundário , Receptores Androgênicos/metabolismo , Transdução de Sinais , Esteroide 17-alfa-Hidroxilase/antagonistas & inibidores , Taxoides/uso terapêutico , Extratos de Tecidos/uso terapêuticoRESUMO
When metastatic prostate cancer progresses despite androgen suppression but symptoms do not yet warrant cytotoxic therapy, abiraterone appears to prolong overall survival and to delay the onset of some cancer-related symptoms. But beware of cardiac and hepatic adverse effects that are inadequately documented.
Assuntos
Antagonistas de Androgênios/efeitos adversos , Androstenóis/efeitos adversos , Neoplasias da Próstata/tratamento farmacológico , Androstenos , Doença Hepática Induzida por Substâncias e Drogas/etiologia , Cardiopatias/induzido quimicamente , Humanos , Masculino , Metástase Neoplásica , Neoplasias da Próstata/patologiaRESUMO
INTRODUCTION: Although most prostate cancers initially respond to castration with luteinizing hormone- releasing analogues or bilateral orchiectomy, progression eventually occurs. Based on the exciting results of several randomized controlled trials (RCTs), it seems that patients with metastatic castration-resistant prostate cancer (mCRPC) might benefit more from treatment withabiraterone. Therefore we conducted a systematic review to evaluate the efficacy and toxicity of abiraterone in the treatment of mCRPC. METHODS: Literature was searched from Embase, PubMed, Web of Science, and Cochrane Library up to July, 2013. Quality of the study was evaluated according to the Cochrane's risk of bias of randomized controlled trial (RCT) tool, then the Grading of Recommendations Assessment, Development and Evaluation (GRADE) System was used to rate the level of evidence. Stata 12.0 was used for statistical analysis. Summary data from RCTs comparing abiraterone plus prednisone versus placebo plus prednisone for mCRPC were meta-analyzed. Pooled hazard ratios (HRs) for overall survival (OS), radiographic progression-free survival (RPFS) and time to PSA progression (TTPP); Pooled risk ratios (RR) for PSA response rate, objective response rate and adverse event were calculated. RESULTS: Ten trials were included in the systematic review; Data of 2,283 patients (1,343 abiraterone; 940 placebo) from two phase 3 trials: COU-AA-301 and COU-AA-302 were meta-analyzed. Compared with placebo, abiraterone significantly prolonged OS (HR, 0.74; 95% confidence interval [CI], 0.66 to 0.84), RPFS (HR, 0.59; 95% CI, 0.48 to 0.74) and time to PSA progression (HR, 0.55; 95% CI, 0.43 to 0.70); it also significantly increased PSA response rate (RR, 3.63; 95% CI, 1.72 to 7.65) and objective response rate (RR, 3.05; 95% CI, 1.51 to 6.15). This meta-analysis suggested that the adverse events caused by abiraterone are acceptable and can be controlled. CONCLUTIOS: Abiraterone significantly prolonged OS, RPFS and time to progression patients with mCRPC, regardless of prior chemotherapy or whether chemotherapy-naive, and no unexpected toxicity was evident. Abiraterone can serve as a new standard therapy for mCRPC.
Assuntos
Androstenóis/uso terapêutico , Antineoplásicos Hormonais/uso terapêutico , Prednisona/uso terapêutico , Neoplasias de Próstata Resistentes à Castração/tratamento farmacológico , Androstenos , Androstenóis/efeitos adversos , Antineoplásicos Hormonais/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Progressão da Doença , Intervalo Livre de Doença , Humanos , Calicreínas/sangue , Masculino , Placebos/uso terapêutico , Antígeno Prostático Específico/sangue , Neoplasias de Próstata Resistentes à Castração/mortalidade , Neoplasias de Próstata Resistentes à Castração/patologiaRESUMO
BACKGROUND: The new generation anti-androgen enzalutamide and the potent CYP17 inhibitor abiraterone have both demonstrated survival benefits in patients with metastatic castration-resistant prostate cancer (CRPC) progressing after docetaxel. Preliminary data on the antitumour activity of abiraterone after enzalutamide have suggested limited activity. The antitumour activity and safety of enzalutamide after abiraterone in metastatic CRPC patients is still unknown. PATIENTS AND METHODS: We retrospectively identified patients treated with docetaxel and abiraterone prior to enzalutamide to investigate the activity and safety of enzalutamide in a more advanced setting. Prostate specific antigen (PSA), radiological and clinical assessments were analysed. RESULTS: 39 patients with metastatic CRPC were identified for this analysis (median age 70years, range: 54-85years). Overall 16 patients (41%) had a confirmed PSA decline of at least 30%. Confirmed PSA declines of ⩾50% and ⩾90% were achieved in 5/39 (12.8%) and 1/39 (2.5%) respectively. Of the 15 patients who responded to abiraterone, two (13.3%) also had a confirmed ⩾50% PSA decline on subsequent enzalutamide. Among the 22 abiraterone-refractory patients, two (9%) achieved a confirmed ⩾50% PSA decline on enzalutamide. CONCLUSION: Our preliminary case series data suggest limited activity of enzalutamide in the post-docetaxel and post-abiraterone patient population.
Assuntos
Androstenóis/uso terapêutico , Feniltioidantoína/análogos & derivados , Neoplasias de Próstata Resistentes à Castração/tratamento farmacológico , Taxoides/uso terapêutico , Idoso , Idoso de 80 Anos ou mais , Androstenos , Androstenóis/efeitos adversos , Benzamidas , Docetaxel , Humanos , Masculino , Pessoa de Meia-Idade , Nitrilas , Feniltioidantoína/efeitos adversos , Feniltioidantoína/uso terapêutico , Antígeno Prostático Específico/metabolismo , Neoplasias de Próstata Resistentes à Castração/metabolismo , Estudos Retrospectivos , Taxoides/efeitos adversos , Resultado do TratamentoRESUMO
On September 5, 2011, abiraterone was approved in the European Union in combination with prednisone or prednisolone for the treatment of metastatic castration-resistant prostate cancer (CRPC) in adult men whose disease has progressed on or after a docetaxel-based chemotherapy regimen. On December 18, 2012, the therapeutic indication was extended to include the use of abiraterone in combination with prednisone or prednisolone for the treatment of metastatic CRPC in adult men who are asymptomatic or mildly symptomatic after failure of androgen deprivation therapy in whom chemotherapy is not yet clinically indicated. Abiraterone is a selective, irreversible inhibitor of cytochrome P450 17α, an enzyme that is key in the production of androgens. Inhibition of androgen biosynthesis deprives prostate cancer cells from important signals for growth, even in cases of resistance to castration. At the time of European Union approval and in a phase III trial in CRPC patients who had failed at least one docetaxel-based chemotherapy regimen, median overall survival for patients treated with abiraterone was 14.8 months versus 10.9 months for those receiving placebo (hazard ratio, 0.65; 95% confidence interval 0.54-0.77; p < .0001). In a subsequent phase III trial in a similar but chemotherapy-naïve patient population, median radiographic progression-free survival was 16.5 months for patients in the abiraterone treatment arm versus 8.3 months for patients in the placebo arm (hazard ratio, 0.53; 95% confidence interval, 0.45-0.62; p < .0001). Abiraterone was most commonly associated with adverse reactions resulting from increased or excessive mineralocorticoid activity. These were generally manageable with basic medical interventions. The most common side effects (affecting more than 10% of patients) were urinary tract infection, hypokalemia, hypertension, and peripheral edema.
Assuntos
Androstenóis/uso terapêutico , Antineoplásicos/uso terapêutico , Neoplasias de Próstata Resistentes à Castração/tratamento farmacológico , Taxoides/uso terapêutico , Adulto , Androstenos , Androstenóis/efeitos adversos , Antineoplásicos/efeitos adversos , Ensaios Clínicos Fase III como Assunto , Progressão da Doença , Docetaxel , Aprovação de Drogas , União Europeia , Humanos , Masculino , Ensaios Clínicos Controlados Aleatórios como Assunto , Taxoides/efeitos adversos , Resultado do TratamentoRESUMO
BACKGROUND: Standard medical castration reduces muscle mass. We sought to characterize body composition changes in men undergoing maximal androgen suppression with and without exogenous gluocorticoids. METHODS: Cross-sectional areas of total fat, visceral fat and muscle were measured on serial CT scans in a post-hoc analysis of patients treated in Phase I/II trials with abiraterone followed by abiraterone and dexamethasone 0.5 mg daily. Linear mixed regression models were used to account for variations in time-on-treatment and baseline body mass index (BMI). RESULTS: Fifty-five patients received a median of 7.5 months abiraterone followed by 5.4 months abiraterone and dexamethasone. Muscle loss was observed on single-agent abiraterone (maximal in patients with baseline BMI >30, -4.3%), but no further loss was observed after addition of dexamethasone. Loss of visceral fat was also observed on single-agent abiraterone, (baseline BMI >30 patients -19.6%). In contrast, addition of dexamethasone led to an increase in central visceral and total fat and BMI in all the patients. INTERPRETATION: Maximal androgen suppression was associated with loss of muscle and visceral fat. Addition of low dose dexamethasone resulted in significant increases in visceral and total fat. These changes could have important quality-of-life implications for men treated with abiraterone.
Assuntos
Antagonistas de Androgênios/efeitos adversos , Androstenóis/efeitos adversos , Composição Corporal/efeitos dos fármacos , Neoplasias da Próstata/tratamento farmacológico , Sarcopenia/induzido quimicamente , Idoso , Idoso de 80 Anos ou mais , Antagonistas de Androgênios/administração & dosagem , Androstenos , Androstenóis/administração & dosagem , Antineoplásicos Hormonais/administração & dosagem , Antineoplásicos Hormonais/efeitos adversos , Humanos , Masculino , Dose Máxima Tolerável , Pessoa de Meia-Idade , Orquiectomia , Neoplasias da Próstata/epidemiologia , Neoplasias da Próstata/cirurgia , Estudos Retrospectivos , Sarcopenia/epidemiologia , Falha de TratamentoRESUMO
PURPOSE: Published efficacy and safety data from clinical trials of three recently approved agents for the management of metastatic castration-resistant prostate cancer (CRPC) are reviewed. SUMMARY: Sipuleucel-T is approved by the Food and Drug Administration (FDA) for the treatment of asymptomatic or minimally symptomatic patients with CRPC. In a placebo-controlled Phase III clinical trial, the use of sipuleucel-T was associated with an average improvement in median overall survival of 4.1 months. Abiraterone acetate and cabazitaxel are approved by FDA as second-line treatments for patients with CRPC who experience disease progression during first-line docetaxel therapy. In Phase III trials, abiraterone acetate was associated with improved overall survival relative to placebo use (14.8 months versus 10.9 months), and cabazitaxel was found to confer an overall survival advantage over mitoxantrone therapy (median survival, 15.1 months versus 12.7 months), corresponding to a 30% reduction in the relative risk of death (hazard ratio, 0.7; 95% confidence interval, 0.59-0.83; p < 0.0001). The three agents range in cost from $40,000 to $93,000 for a full course of therapy. Sipuleucel therapy entails leukapheresis procedures for the collection of autologous cells used in dose preparation, requiring careful planning and coordination of care. CONCLUSION: Sipuleucel-T, abiraterone acetate, and cabazitaxel offer new options for the treatment of patients with CRPC, including those with disease resistant to standard first-line therapies. The agents' varying administration requirements, as well as patient-specific factors and cost issues, are key considerations in the drug selection process.
Assuntos
Androstenóis/uso terapêutico , Antineoplásicos/uso terapêutico , Vacinas Anticâncer/uso terapêutico , Neoplasias da Próstata/tratamento farmacológico , Taxoides/uso terapêutico , Extratos de Tecidos/uso terapêutico , Androstenos , Androstenóis/administração & dosagem , Androstenóis/efeitos adversos , Antineoplásicos/administração & dosagem , Antineoplásicos/efeitos adversos , Vacinas Anticâncer/administração & dosagem , Vacinas Anticâncer/efeitos adversos , Ensaios Clínicos como Assunto , Honorários Farmacêuticos , Humanos , Masculino , Orquiectomia , Taxoides/administração & dosagem , Taxoides/efeitos adversos , Extratos de Tecidos/administração & dosagem , Extratos de Tecidos/efeitos adversosRESUMO
BACKGROUND: Abiraterone strongly inhibits androgen synthesis but may lead to an increase in mineralocorticoid hormones that may impair its long term tolerability in patients with prostate cancer. How to implement available therapies in the management and prevention of these potential side effects is a matter of current clinical research. METHODS: The acute and long term consequences of mineralocorticoid excess and the effects of available treatments have been reviewed. Prospective studies in which abiraterone was employed were identified to assess the frequency and severity of the mineralocorticoid excess syndrome and the efficacy of ameliorating therapeutic approaches. RESULTS: Glucocorticoids to inhibit the ACTH increase that drives mineralocorticoid synthesis and mineralocorticoid receptor (MR) antagonists can be used in the management of the abiraterone-induced mineralocorticoid excess syndrome. Phase I and II trials of abiraterone without additional therapies revealed that mineralocorticoid excess symptoms occur in the majority of patients. Eplerenone, a specific MR antagonist, seems to be effective but it does not control the mineralocorticoid excess. Glucorticoid supplementation to control ACTH drive is therefore needed. In several randomized trials the addition of prednisone (10mg daily) to abiraterone was not able to prevent mineralocorticoid excess syndrome in many cases and thus cannot be considered the gold standard. CONCLUSION: At present, the best conceivable treatment for managing the abiraterone-induced mineralocorticoid excess consists of the administration of glucocorticoid replacement at the lowest effective dose ± MR antagonists and salt deprivation. The drug doses should be modulated by monitoring blood pressure, fluid retention and potassium levels during therapy.
Assuntos
Hormônio Adrenocorticotrópico/efeitos adversos , Androstenóis/efeitos adversos , Síndrome de Excesso Aparente de Minerolocorticoides/induzido quimicamente , Neoplasias da Próstata/tratamento farmacológico , Hormônio Adrenocorticotrópico/uso terapêutico , Androstenos , Androstenóis/uso terapêutico , Humanos , Masculino , Síndrome de Excesso Aparente de Minerolocorticoides/metabolismo , Mineralocorticoides/metabolismo , Neoplasias da Próstata/metabolismoRESUMO
Advanced prostate cancer that progresses under androgen deprivation therapy has long been thought to be refractory to further hormonal treatment. The identification of the mechanism of cancer cells has revolutionized this understanding. Today it is known that castration-resistant prostate cancer (CRPC) still receives signals through the androgen receptor transduction pathways and furthermore is sensitive to hormone therapy. New substances, such as abiraterone, enzalutamide (MDV3100) and TAK 700 target these mechanisms of resistance of cancer cells, stop testosterone production and show not only better tolerance but also effective antitumor activity. Due to the heterogeneity of tumors with cells in varying states of differentiation, the treatment of CRPC with androgen deprivation therapy remains a cornerstone of disease management. To what extent the experimental findings and the recommendations in the guidelines are put into practice was the subject of a survey among urologists analyzing their treatment strategies with CRPC patients.
Assuntos
Antagonistas de Androgênios/uso terapêutico , Antineoplásicos Hormonais/uso terapêutico , Orquiectomia , Neoplasias da Próstata/tratamento farmacológico , Neoplasias da Próstata/fisiopatologia , Antagonistas de Androgênios/efeitos adversos , Androstenos , Androstenóis/efeitos adversos , Androstenóis/uso terapêutico , Antineoplásicos Hormonais/efeitos adversos , Benzamidas , Biomarcadores Tumorais/sangue , Progressão da Doença , Resistencia a Medicamentos Antineoplásicos , Humanos , Imidazóis/efeitos adversos , Imidazóis/uso terapêutico , Masculino , Naftalenos/efeitos adversos , Naftalenos/uso terapêutico , Nitrilas , Feniltioidantoína/efeitos adversos , Feniltioidantoína/análogos & derivados , Feniltioidantoína/uso terapêutico , Próstata/efeitos dos fármacos , Próstata/fisiopatologia , Antígeno Prostático Específico/sangueRESUMO
OBJECTIVE: To review the activity of 3 new agents approved for the management of advanced castration-resistant prostate cancer (CRPC): sipuleucel-T, cabazitaxel, and abiraterone acetate. DATA SOURCES: Literature was accessed through MEDLINE (1977-June 2012) and abstracts from the American Society of Clinical Oncology (2000-2012) using the terms castration-resistant and hormone-refractory prostate cancer, sipuleucel-T, cabazitaxel, abiraterone, Provenge, Jevtana, and Zytiga. Reference citations from publications identified were also reviewed. STUDY SELECTION AND DATA EXTRACTION: Articles identified from the data sources in English on human subjects were evaluated. DATA SYNTHESIS: Options for patients with CRPC have been limited, with little to offer those who failed or could not tolerate docetaxel-based therapy. Three new drugs, with very different mechanisms of action, have changed that and will undoubtedly change the treatment paradigm for these patients. Each agent has demonstrated an impact on patient survival. Sipuleucel-T, the first immunotherapy approved for treatment of CRPC, improved median overall survival by 4.1 months and reduced the risk of death by 22% in a placebo-controlled trial of asymptomatic patients. Sipuleucel-T can be administered prior to docetaxel-based therapy. Cabazitaxel, a taxane chemotherapy agent, improved median overall survival by 2.4 months and reduced the risk of death by 30% in a Phase 3 trial of patients whose cancer progressed during or after docetaxel-based therapy. Abiraterone acetate, a hormonal therapy, improved median overall survival by 3.9 months and reduced the risk of death by 35% in patients with relapse during or after docetaxel-based therapy. CONCLUSIONS: The advent of new agents for the management of advanced CRPC has increased the choices for patients whose options were limited. Additional experience will determine the optimal sequencing of these agents, their roles in combination therapy, and their activity in patients with earlier disease.
Assuntos
Androstenóis/administração & dosagem , Antineoplásicos/administração & dosagem , Neoplasias da Próstata/tratamento farmacológico , Taxoides/administração & dosagem , Extratos de Tecidos/administração & dosagem , Androstenos , Androstenóis/efeitos adversos , Androstenóis/farmacocinética , Antineoplásicos/efeitos adversos , Antineoplásicos/farmacocinética , Castração , Humanos , Masculino , Neoplasias da Próstata/metabolismo , Taxoides/efeitos adversos , Taxoides/farmacocinética , Extratos de Tecidos/efeitos adversos , Extratos de Tecidos/farmacocinéticaRESUMO
There is no standard treatment for metastatic prostate cancer that progresses despite castration and cytotoxic chemotherapy. Abiraterone inhibits both testicular and extratesticular androgen synthesis. It has been approved in the European Union for use in this situation, in which treatment options are extremely limited. Clinical evaluation is based on a double-blind comparative trial of good methodological quality that included 1195 patients. The median overall survival time was 4 months longer in the group treated with abiraterone + prednisone (or prednisolone) than in the group treated with placebo + prednisone (or prednisolone): 15.8 versus 11.2 months. The addition of prednisone (or prednisolone) reduced but did not eliminate the effects of hyperaldosteronism induced by abiraterone; oedema occurred in 26.7% of patients, arterial hypertension in 8.5%, and hypokalaemia in 17.1%. Moderate hepatotoxicity was reported with abiraterone and needs to be better assessed. Abiraterone was also associated with cardiac arrhythmias (7.2% versus 4.6% with placebo) and heart failure (1% versus 0.3%). Abiraterone is metabolised by cytochrome P450 isoenzyme CYP3A4 and inhibits isoenzyme CYP2D6, resulting in a high potential for drug interactions. Treatment is somewhat inconvenient. Abiraterone must be taken between meals, serum potassium levels must be monitored, and care must be taken to avoid interactions. Overall, the known risks of abiraterone appear to be acceptable in view of its efficacy, but patients must be carefully monitored. Abiraterone is one option to discuss with patients with metastatic prostate cancer after other treatments fail.
Assuntos
Androstenóis/efeitos adversos , Neoplasias da Próstata/tratamento farmacológico , Androstenos , Interações Medicamentosas , Humanos , Masculino , Metástase Neoplásica , Prednisona/administração & dosagem , Neoplasias da Próstata/mortalidade , Neoplasias da Próstata/patologiaRESUMO
PURPOSE: To evaluate pharmacokinetics, safety, and tolerability of abiraterone acetate (AA) in healthy men. METHODS: Two phase I studies (dose-escalation study and dose-proportionality study) were conducted in healthy men aged 18-55 years. All subjects received 4 consecutive single doses of AA (250, 500, 750 and 1,000 mg). The dose-escalation study subjects (N = 33) received AA doses in a sequential manner, starting with the lowest dose. The dose-proportionality study subjects (N = 32) were randomly allocated (1:1:1:1) to receive each of the 4 doses in a four-way crossover design. RESULTS: A dose-related increase in abiraterone exposure was observed in both studies. Over the evaluated dose range, the mean abiraterone maximum plasma concentrations increased from 26 to 112 ng/mL in dose-escalation study and from 40 to 125 ng/mL in dose-proportionality study; the mean area under the plasma concentration-time curve from 0 to the last measurable plasma concentration increased from 155 to 610 ng.h/mL in dose-escalation study, and from 195 to 607 ng.h/mL in dose-proportionality study. In the dose-proportionality study, abiraterone exposure was dose proportional between 1,000 and 750 mg doses; however, the exposure was slightly greater than dose proportional when exposures at 500 and 250 mg doses were compared with the exposure at 1,000 mg. Single doses of AA were well tolerated in healthy men, and safety profile was consistent with its known toxicities in CRPC patients. CONCLUSION: Systemic exposure to abiraterone increased with increasing doses of AA (250-1,000 mg) in healthy men; AA was well tolerated in this population.
Assuntos
Androstenóis/farmacocinética , Adolescente , Adulto , Androstenos , Androstenóis/efeitos adversos , Relação Dose-Resposta a Droga , Humanos , Hormônio Luteinizante/sangue , Masculino , Pessoa de Meia-Idade , Testosterona/sangueAssuntos
Androstenóis/uso terapêutico , Antineoplásicos Hormonais/uso terapêutico , Inibidores Enzimáticos/uso terapêutico , Neoplasias da Próstata/tratamento farmacológico , Androstenos , Androstenóis/efeitos adversos , Antineoplásicos Hormonais/efeitos adversos , Ensaios Clínicos Fase III como Assunto , Contraindicações , Aprovação de Drogas , Inibidores Enzimáticos/efeitos adversos , Humanos , MasculinoRESUMO
OBJECTIVE: First clinical experiences with abiraterone and cabazitaxel for the treatment of metastatic castration-resistant prostate cancer patients following docetaxel chemotherapy are reported. PATIENTS AND METHODS: We describe PSA response rates and disease control rates determined by imaging studies at 3 months as well as side effects in the daily routine. All patients were treated within the"compassionate use" programs of cabazitaxel and abiraterone or treated according to their inclusion and exclusion criteria at the "Technische Universität München". RESULTS: Of 54 patients, 15 were treated with cabazitaxel and 39 with abiraterone. In patients treated with cabazitaxel, after 3 months of therapy the PSA reduction rate > 50% was 46.2%, the PSA progression rate was 15.4%, and the disease control rate was 83.3%. Main grade 3/4 hematotoxicities were neutropenia (40%) and anemia (20%). Febrile neutropenia was observed in 2 of 15 (13.3%) patients. Main non-hematological grade 3/4 toxicities were diarrhea (13.3%) and polyneuropathy (13.3%). In patients treated with abiraterone, after 3 months of therapy the PSA reduction rate >50% was 35.1%, the PSA progression rate was 46.0%, and the disease control rate was 47.1%. Main grade 3/4 hematotoxicities were anemia (5.1%) and thrombocytopenia (5.1%). Main non-hematological toxicities were fatigue (20.5%), sweating (17.9%), and constipation (10.3%). CONCLUSION: Utilization of cabazitaxel and abiraterone in the daily routine show response rates comparable to their approval studies with acceptable side effects.
Assuntos
Androstenóis/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Ensaios de Uso Compassivo , Orquiectomia , Neoplasias da Próstata/tratamento farmacológico , Taxoides/administração & dosagem , Idoso , Androstenos , Androstenóis/efeitos adversos , Biomarcadores Tumorais/sangue , Progressão da Doença , Docetaxel , Relação Dose-Resposta a Droga , Resistencia a Medicamentos Antineoplásicos , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Gradação de Tumores , Estadiamento de Neoplasias , Prednisona/administração & dosagem , Prednisona/efeitos adversos , Antígeno Prostático Específico/sangue , Neoplasias da Próstata/sangue , Neoplasias da Próstata/patologia , Neoplasias da Próstata/cirurgia , Taxoides/efeitos adversosRESUMO
PURPOSE: Persistent androgen signaling is implicated in castrate-resistant prostate cancer (CRPC) progression. This study aimed to evaluate androgen signaling in bone marrow-infiltrating cancer and testosterone in blood and bone marrow and to correlate with clinical observations. PATIENTS AND METHODS: This was an open-label, observational study of 57 patients with bone-metastatic CRPC who underwent transiliac bone marrow biopsy between October 2007 and March 2010. Patients received oral abiraterone acetate (1 g) once daily and prednisone (5 mg) twice daily. Androgen receptor (AR) and CYP17 expression were assessed by immunohistochemistry, testosterone concentration by mass spectrometry, AR copy number by polymerase chain reaction, and TMPRSS2-ERG status by fluorescent in situ hybridization in available tissues. RESULTS: Median overall survival was 555 days (95% CI, 440 to 965+ days). Maximal prostate-specific antigen decline ≥ 50% occurred in 28 (50%) of 56 patients. Homogeneous, intense nuclear expression of AR, combined with ≥ 10% CYP17 tumor expression, was correlated with longer time to treatment discontinuation (> 4 months) in 25 patients with tumor-infiltrated bone marrow samples. Pretreatment CYP17 tumor expression ≥ 10% was correlated with increased bone marrow aspirate testosterone. Blood and bone marrow aspirate testosterone concentrations declined to less than picograms-per-milliliter levels and remained suppressed at progression. CONCLUSION: The observed pretreatment androgen-signaling signature is consistent with persistent androgen signaling in CRPC bone metastases. This is the first evidence that abiraterone acetate achieves sustained suppression of testosterone in both blood and bone marrow aspirate to less than picograms-per-milliliter levels. Potential admixture of blood with bone marrow aspirate limits our ability to determine the origin of measured testosterone.