RESUMO
BACKGROUND: Mutations in the androgen receptor (AR) ligand-binding domain (LBD), such as F877L and T878A, have been associated with resistance to next-generation AR-directed therapies. ARN-509-001 was a phase I/II study that evaluated apalutamide activity in castration-resistant prostate cancer (CRPC). Here, we evaluated the type and frequency of 11 relevant AR-LBD mutations in apalutamide-treated CRPC patients. PATIENTS AND METHODS: Blood samples from men with nonmetastatic CRPC (nmCRPC) and metastatic CRPC (mCRPC) pre- or post-abiraterone acetate and prednisone (AAP) treatment (≥6 months' exposure) were evaluated at baseline and disease progression in trial ARN-509-001. Mutations were detected in circulating tumor DNA using a digital polymerase chain reaction-based method known as BEAMing (beads, emulsification, amplification and magnetics) (Sysmex Inostics' GmbH). RESULTS: Of the 97 total patients, 51 had nmCRPC, 25 had AAP-naïve mCRPC, and 21 had post-AAP mCRPC. Ninety-three were assessable for the mutation analysis at baseline and 82 of the 93 at progression. The overall frequency of detected AR mutations at baseline was 7/93 (7.5%) and at progression was 6/82 (7.3%). Three of the 82 (3.7%) mCRPC patients (2 AAP-naïve and 1 post-AAP) acquired AR F877L during apalutamide treatment. At baseline, 3 of the 93 (3.2%) post-AAP patients had detectable AR T878A, which was lost after apalutamide treatment in 1 patient who continued apalutamide treatment for 12 months. CONCLUSIONS: The overall frequency of detected mutations at baseline (7.5%) and progression (7.3%) using the sensitive BEAMing assay was low, suggesting that, based on this assay, AR-LBD mutations such as F877L and T878A are not common contributors to de novo or acquired resistance to apalutamide. CLINICALTRIALS.GOV IDENTIFIER: NCT01171898.
Assuntos
Antagonistas de Androgênios/uso terapêutico , Mutação Puntual , Neoplasias de Próstata Resistentes à Castração/tratamento farmacológico , Neoplasias de Próstata Resistentes à Castração/genética , Receptores Androgênicos/genética , Tioidantoínas/uso terapêutico , Idoso , Idoso de 80 Anos ou mais , DNA Tumoral Circulante/genética , Humanos , Masculino , Pessoa de Meia-IdadeRESUMO
BACKGROUND: Androgen receptor (AR) signaling and incomplete inhibition of estrogen signaling may contribute to metastatic breast cancer (MBC) resistance to a nonsteroidal aromatase inhibitor (NSAI; letrozole or anastrozole). We assessed whether combined inhibition of androgen biosynthesis with abiraterone acetate plus prednisone and estradiol synthesis with exemestane (E) may be of clinical benefit to postmenopausal patients with NSAI-pretreated estrogen receptor-positive (ER+) MBC. PATIENTS AND METHODS: Patients (N = 297) were stratified by the number of prior therapies for metastatic disease (0-1 versus 2) and by prior NSAI use (adjuvant versus metastatic), and randomized (1 : 1 : 1) to receive oral once daily 1000 mg abiraterone acetate plus 5 mg prednisone (AA) versus AA with 25 mg E (AAE) versus 25 mg E alone (E). Each treatment arm was well balanced with regard to the proportion of patients with AR-positive breast cancer. The primary end point was progression-free survival (PFS). Secondary end points included overall survival, clinical benefit rate, duration of response, and overall response rate. RESULTS: There was no significant difference in PFS with AA versus E (3.7 versus 3.7 months; hazard ratio [HR] = 1.1; 95% confidence interval [CI] 0.82-1.60; P = 0.437) or AAE versus E (4.5 versus 3.7 months; HR = 0.96; 95% CI 0.70-1.32; P = 0.794). Increased serum progesterone concentrations were observed in both arms receiving AA, but not with E. Grade 3 or 4 treatment-emergent adverse events associated with AA, including hypokalemia and hypertension, were less common in patients in the E (2.0% and 2.9%, respectively) and AA arms (3.4% and 1.1%, respectively) than in the AAE arm (5.8% for both). CONCLUSIONS: Adding AA to E in NSAI-pretreated ER+ MBC patients did not improve PFS compared with treatment with E. An AA-induced progesterone increase may have contributed to this lack of clinical activity. CLINICALTRIALSGOV: NCT01381874.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias Ósseas/tratamento farmacológico , Neoplasias da Mama/tratamento farmacológico , Acetato de Abiraterona/administração & dosagem , Adulto , Idoso , Idoso de 80 Anos ou mais , Androstadienos/administração & dosagem , Neoplasias Ósseas/metabolismo , Neoplasias Ósseas/mortalidade , Neoplasias Ósseas/secundário , Neoplasias da Mama/metabolismo , Neoplasias da Mama/mortalidade , Neoplasias da Mama/patologia , Intervalo Livre de Doença , Feminino , Humanos , Estimativa de Kaplan-Meier , Metástase Linfática , Pessoa de Meia-Idade , Pós-Menopausa , Modelos de Riscos Proporcionais , Receptores de Estrogênio/metabolismo , Resultado do TratamentoRESUMO
BACKGROUND: The usefulness of Gleason score (<8 or ≥8) at initial diagnosis as a predictive marker of response to abiraterone acetate (AA) plus prednisone in patients with metastatic castration-resistant prostate cancer (mCRPC) was explored retrospectively. PATIENTS AND METHODS: Initial diagnosis Gleason score was obtained in 1048 of 1195 (COU-AA-301, post-docetaxel) and 996 of 1088 (COU-AA-302, chemotherapy-naïve) patients treated with AA 1 g plus prednisone 5 mg twice daily by mouth or placebo plus prednisone. Efficacy end points included radiographic progression-free survival (rPFS) and overall survival (OS). Distributions and medians were estimated by Kaplan-Meier method and hazard ratio (HR) and 95% confidence interval (CI) by Cox model. RESULTS: Baseline characteristics were similar across studies and treatment groups. Regardless of Gleason score, AA treatment significantly improved rPFS in post-docetaxel [Gleason score <8: median, 6.4 versus 5.5 months (HR = 0.70; 95% CI 0.56-0.86), P = 0.0009 and Gleason score ≥8: median, 5.6 versus 2.9 months (HR = 0.58; 95% CI 0.48-0.72), P < 0.0001] and chemotherapy-naïve patients [Gleason score <8: median, 16.5 versus 8.2 months (HR = 0.50; 95% CI 0.40-0.62), P < 0.0001 and Gleason score ≥8: median, 13.8 versus 8.2 months (HR = 0.61; 95% CI 0.49-0.76), P < 0.0001]. Clinical benefit of AA treatment was also observed for OS, prostate-specific antigen (PSA) response, objective response and time to PSA progression across studies and Gleason score subgroups. CONCLUSION: OS and rPFS trends demonstrate AA treatment benefit in patients with pre- or post-chemotherapy mCRPC regardless of Gleason score at initial diagnosis. The initial diagnostic Gleason score in patients with mCRPC should not be considered in the decision to treat with AA, as tumour metastases may no longer reflect the histology at the time of diagnosis. CLINICAL TRIALS NUMBER: COU-AA-301 (NCT00638690); COU-AA-302 (NCT00887198).
Assuntos
Acetato de Abiraterona/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Neoplasias de Próstata Resistentes à Castração/diagnóstico , Neoplasias de Próstata Resistentes à Castração/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Androstenóis/administração & dosagem , Intervalo Livre de Doença , Método Duplo-Cego , Humanos , Masculino , Pessoa de Meia-Idade , Gradação de Tumores , Metástase Neoplásica , Prednisona/administração & dosagem , Neoplasias de Próstata Resistentes à Castração/patologiaRESUMO
BACKGROUND: Few prognostic models for overall survival (OS) are available for patients with metastatic castration-resistant prostate cancer (mCRPC) treated with recently approved agents. We developed a prognostic index model using readily available clinical and laboratory factors from a phase III trial of abiraterone acetate (hereafter abiraterone) in combination with prednisone in post-docetaxel mCRPC. PATIENTS AND METHODS: Baseline data were available from 762 patients treated with abiraterone-prednisone. Factors were assessed for association with OS through a univariate Cox model and used in a multivariate Cox model with a stepwise procedure to identify those of significance. Data were validated using an independent, external, population-based cohort. RESULTS: Six risk factors individually associated with poor prognosis were included in the final model: lactate dehydrogenase > upper limit of normal (ULN) [hazard ratio (HR) = 2.31], Eastern Cooperative Oncology Group performance status of 2 (HR = 2.19), presence of liver metastases (HR = 2.00), albumin ≤4 g/dl (HR = 1.54), alkaline phosphatase > ULN (HR = 1.38) and time from start of initial androgen-deprivation therapy to start of treatment ≤36 months (HR = 1.30). Patients were categorized into good (n = 369, 46%), intermediate (n = 321, 40%) and poor (n = 107, 13%) prognosis groups based on the number of risk factors and relative HRs. The C-index was 0.70 ± 0.014. The model was validated by the external dataset (n = 286). CONCLUSION: This analysis identified six factors used to model survival in mCRPC and categorized patients into three distinct risk groups. Prognostic stratification with this model could assist clinical practice decisions for follow-up and monitoring, and may aid in clinical trial design. TRIAL REGISTRATION NUMBERS: NCT00638690.
Assuntos
Acetato de Abiraterona/uso terapêutico , Antineoplásicos/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Prednisona/uso terapêutico , Neoplasias de Próstata Resistentes à Castração/tratamento farmacológico , Acetato de Abiraterona/efeitos adversos , Antineoplásicos/efeitos adversos , Intervalo Livre de Doença , Método Duplo-Cego , Humanos , Masculino , Prednisona/efeitos adversos , Modelos de Riscos ProporcionaisRESUMO
BACKGROUND: Fatigue is a common, debilitating side-effect of prostate cancer and its treatment. Patient-reported fatigue was evaluated as part of COU-AA-301, a randomized, placebo-controlled, phase III trial of abiraterone acetate and prednisone versus placebo and prednisone in metastatic castration-resistant prostate cancer (mCRPC) patients after docetaxel chemotherapy. This is the first phase III study in advanced prostate cancer to evaluate fatigue outcomes using a validated fatigue-specific instrument. PATIENTS AND METHODS: The Brief Fatigue Inventory (BFI) questionnaire was used to measure patient-reported fatigue intensity and fatigue interference with activities of daily life. All analyses were conducted using prespecified responder definitions of clinically meaningful changes. RESULTS: A total of 797 patients were randomized to abiraterone acetate and prednisone, and 398 were randomized to placebo and prednisone. Compared with prednisone alone, in patients with clinically significant fatigue at baseline, abiraterone acetate and prednisone significantly increased the proportion of patients reporting improvement in fatigue intensity (58.1% versus 40.3%, P = 0.0001), improved fatigue interference (55.0% versus 38.0%, P = 0.0075), and accelerated improvement in fatigue intensity (median 59 days versus 194 days, P = 0.0155). CONCLUSIONS: In patients with mCRPC progressing after docetaxel chemotherapy, abiraterone acetate and prednisone yielded clinically meaningful improvements in patient-reported fatigue compared with prednisone alone.
Assuntos
Androstadienos/administração & dosagem , Fadiga/tratamento farmacológico , Neoplasias da Próstata/tratamento farmacológico , Taxoides/administração & dosagem , Acetato de Abiraterona , Castração , Docetaxel , Fadiga/induzido quimicamente , Fadiga/epidemiologia , Fadiga/patologia , Humanos , Masculino , Metástase Neoplásica/tratamento farmacológico , Estadiamento de Neoplasias , Prednisona/administração & dosagem , Neoplasias da Próstata/complicações , Neoplasias da Próstata/epidemiologia , Neoplasias da Próstata/patologia , Inquéritos e Questionários , Taxoides/efeitos adversosRESUMO
BACKGROUND: We analyzed the potential of abiraterone acetate (henceforth abiraterone) to reduce androgen levels below lower limits of quantification (LLOQ) and explored the association with changes in PSA decline in metastatic castration-resistant prostate cancer (mCRPC) patients. METHODS: COU-AA-301 is a 2:1 randomized, double-blind, placebo-controlled study comparing abiraterone (1000 mg q.d.) plus low-dose prednisone (5 mg b.i.d.) with placebo plus prednisone in mCRPC patients post docetaxel. Serum testosterone, androstenedione and dehydroepiandrosterone sulfate from baseline to week 12 were measured by novel ultrasensitive two-dimensional liquid chromatography coupled to tandem mass spectrometry assays in a subset of subjects in each arm (abiraterone plus prednisone, n=80; prednisone, n=38). The association between PSA response (< or =50% baseline) and undetectable androgens (week 12 androgen level below LLOQ) was analyzed using logistic regression. RESULTS: A significantly greater reduction in serum androgens was observed with abiraterone plus prednisone versus prednisone (all P < or = 0.0003), reaching undetectable levels for testosterone (47.2% versus 0%, respectively). A positive association was observed between achieving undetectable serum androgens and PSA decline (testosterone: odds ratio=1.54; 95% confidence interval: 0.546-4.347). Reduction of androgens to undetectable levels did not occur in all patients achieving a PSA response, and a PSA response did not occur in all patients achieving undetectable androgen levels. CONCLUSIONS: Abiraterone plus prednisone significantly reduced serum androgens, as measured by ultrasensitive assays and was generally associated with PSA response. However, androgen decline did not uniformly predict PSA decline suggesting ligand-independent or other mechanisms for mCRPC progression.
Assuntos
Androgênios/sangue , Androstenos/uso terapêutico , Calicreínas/sangue , Antígeno Prostático Específico/sangue , Neoplasias de Próstata Resistentes à Castração/sangue , Neoplasias de Próstata Resistentes à Castração/tratamento farmacológico , Acetato de Abiraterona , Método Duplo-Cego , Humanos , Masculino , Prednisona/uso terapêutico , Testosterona/sangue , Resultado do TratamentoRESUMO
BACKGROUND: Visceral disease, non-nodal soft-tissue metastases predominantly involving the lung and liver, is a negative prognostic factor in patients with metastatic castration-resistant prostate cancer (mCRPC). An exploratory analysis of COU-AA-301 assessed whether abiraterone acetate (AA) improved overall survival (OS) in mCRPC patients with visceral disease progressing post docetaxel. METHODS: In COU-AA-301, post-docetaxel mCRPC patients were randomized 2:1 to AA 1000 mg (n=797) or placebo (n=398) once daily, each with prednisone 5 mg b.i.d. The primary end point was OS; secondary end points included radiographic progression-free survival (rPFS), PSA response rate and objective response rate (ORR). Treatment effects in visceral disease (n=352) and non-visceral disease (n=843) subsets were examined using final data (775 OS events). RESULTS: AA plus prednisone produced similar absolute improvement in median OS in patients with (4.6 months) and without (4.8 months) visceral disease versus prednisone; hazard ratios (HRs) were 0.79 (95% confidence interval (CI): 0.60-1.05; P=0.102) and 0.69 (95% CI: 0.58-0.83; P<0.0001), respectively. Treatment with AA plus prednisone significantly and comparably improved secondary endpoint outcomes versus prednisone in both the subsets: the HRs for rPFS were 0.60 (95% CI: 0.46-0.78; P=0.0002) and 0.68 (95% CI: 0.58-0.80; P<0.0001) in visceral and non-visceral disease subsets, respectively. PSA response rates were 28% versus 7% in the visceral disease subsets and 30% versus 5% in the non-visceral disease subsets (both P<0.0001), and ORRs were 11% versus 0% (P=0.0058) and 19% versus 5% (P=0.0010), respectively. The incidence of grade 3/4 adverse events was similar between the subsets and between the treatment arms in each subset. Adverse events related to CYP17 blockade were increased in the AA arms and were similar in patients with or without visceral disease. CONCLUSIONS: AA plus prednisone provides significant clinical benefit, including improvements in OS and secondary end points, in post-docetaxel mCRPC patients with or without baseline visceral disease. The presence of visceral disease does not preclude clinical benefit from abiraterone.
Assuntos
Androstadienos/uso terapêutico , Antineoplásicos Hormonais/uso terapêutico , Neoplasias de Próstata Resistentes à Castração/tratamento farmacológico , Neoplasias de Próstata Resistentes à Castração/patologia , Vísceras/patologia , Acetato de Abiraterona , Adulto , Idoso , Idoso de 80 Anos ou mais , Androstadienos/administração & dosagem , Androstadienos/efeitos adversos , Antineoplásicos Hormonais/administração & dosagem , Antineoplásicos Hormonais/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Docetaxel , Humanos , Masculino , Pessoa de Meia-Idade , Gradação de Tumores , Metástase Neoplásica , Prednisona/administração & dosagem , Neoplasias de Próstata Resistentes à Castração/mortalidade , Fatores de Risco , Taxoides/administração & dosagem , Resultado do TratamentoRESUMO
PURPOSE: Abiraterone is the active metabolite of the pro-drug abiraterone acetate (AA) and a selective inhibitor of CYP17, a key enzyme in testosterone synthesis, and improves overall survival in postdocetaxel metastatic castration-resistant prostate cancer (mCRPC). This open-label, single-arm phase 1b study was conducted to assess the effect of AA and abiraterone on the QT interval. METHODS: The study was conducted in 33 patients with mCRPC. Patients received AA 1,000 mg orally once daily + prednisone 5 mg orally twice daily. Electrocardiograms (ECGs) were collected in triplicate using 12-lead Holter monitoring. Baseline ECGs were obtained on Cycle 1 Day-1. Serial ECG recordings and time-matched pharmacokinetic (PK) blood samples were collected over 24 h on Cycle 1 Day 1 and Cycle 2 Day 1. Serial PK blood samples were also collected over 24 h on Cycle 1 Day 8. RESULTS: After AA administration, the upper bound of the 2-sided 90 % confidence interval (CI) for the mean baseline-adjusted QTcF change was <10 ms; no patients discontinued due to QTc prolongation or adverse events. No apparent relationship between change in QTcF and abiraterone plasma concentrations was observed [estimated slope (90 % CI): 0.0031 (-0.0040, 0.0102)]. CONCLUSIONS: There is no significant effect of AA plus prednisone on the QT/QTc interval in patients with mCRPC.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Síndrome do QT Longo , Neoplasias Hormônio-Dependentes/tratamento farmacológico , Neoplasias da Próstata/tratamento farmacológico , Acetato de Abiraterona , Androgênios/metabolismo , Androstadienos/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/sangue , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Esquema de Medicação , Eletrocardiografia/efeitos dos fármacos , Frequência Cardíaca/efeitos dos fármacos , Humanos , Síndrome do QT Longo/induzido quimicamente , Masculino , Neoplasias Hormônio-Dependentes/sangue , Neoplasias Hormônio-Dependentes/enzimologia , Neoplasias Hormônio-Dependentes/patologia , Orquiectomia , Prednisona/administração & dosagem , Neoplasias da Próstata/sangue , Neoplasias da Próstata/enzimologia , Neoplasias da Próstata/patologia , Esteroide 17-alfa-Hidroxilase/antagonistas & inibidoresRESUMO
Amsacrine is an antineoplastic drug used in the treatment of acute adult leukemias. To assess its carcinogenic potential, groups of 50 male and 50 female rats were administered amsacrine by lateral tail vein injection at 0 (vehicle control), 0.25, 1, or 3 mg/kg once daily for 5 days, followed by a 23-day recovery period. This cycle of dosing and recovery was repeated a total of six times. The animals were then maintained without dosing for an 18-month observation period. During the dosing phase, signs of toxicity were limited to the 3 mg/kg animals and included alopecia, diarrhea, injection site lesions, and skin and subcutaneous nodules. Statistically significant reductions in body weight gain and food consumption also occurred at 3 mg/kg during each 5-day dosing period followed by recovery during the latter 3 weeks of each cycle. Except for skin and subcutaneous nodules, signs of toxicity in the 3 mg/kg animals ultimately disappeared during the 18-month observation phase. Survival at study termination for the vehicle control, 0.25, 1, and 3 mg/kg groups was 56, 52, 34, and 0%, respectively, in males, and 64, 48, 54, and 4%, respectively, in females. Mortality was primarily due to bone marrow suppression during the dosing phase, chronic progressive nephropathy, or development of tumors. Incidences of the following tumors were significantly increased in the 3 mg/kg groups of both sexes (Fisher exact test, two-tailed, p < 0.01): all malignancies; all tumors of the small intestine, adenocarcinoma and adenoma of the small intestine, all tumors of the skin, and squamous cell papilloma. Other tumor incidences that were significantly increased in the 3 mg/kg males were thymoma and multiple neoplastic histotypes of the skin and adnexa including basal cell tumor, fibroma, sebaceous gland adenoma, and squamous cell carcinoma. A disproportionate number of the skin tumors were located on the tail, suggesting a localized tissue concentration effect. In the 3 mg/kg females, significantly increased tumor incidences also included all tumors of the mammary gland, adenocarcinoma of the mammary gland, all tumors of the uterine horn, and endometrial stromal polyps of the uterine horn. The 1 mg/kg males had significantly increased incidences of all tumors of the small intestine and skin, adenocarcinoma of the small intestine, and fibroma of the skin. Fibroma of the skin was also significantly increased in the 0.25 mg/kg males. Incidences of all tumors and all benign tumors were significantly increased in the 1 mg/kg females. There were no significantly increased tumor incidences in the 0.25 mg/kg females. The results of this study show that amsacrine is carcinogenic in Wistar rats. Target organs for tumorigenicity include small intestine, skin, mammary gland, thymus, and uterus.