Evaluation of Clinically Relevant Drug-Drug Interactions and Population Pharmacokinetics of Darolutamide in Patients with Nonmetastatic Castration-Resistant Prostate Cancer: Results of Pre-Specified and Post Hoc Analyses of the Phase III ARAMIS Trial.

BACKGROUND: Darolutamide, an androgen receptor antagonist with a distinct molecular structure, significantly prolonged metastasis-free survival versus placebo in the phase III ARAMIS study in men with nonmetastatic castration-resistant prostate cancer (nmCRPC). In this population, polypharmacy for age-related comorbidities is common and may increase drug-drug interaction (DDI) risks. Preclinical/phase I study data suggest darolutamide has a low DDI potential-other than breast cancer resistance protein/organic anion transporter protein substrates (e.g., statins), no clinically relevant effect on comedications is expected. OBJECTIVE: Our objective was to evaluate the effect of commonly administered drugs on the pharmacokinetics of darolutamide and the effect of comedications potentially affected by darolutamide on safety in patients with nmCRPC. PATIENTS AND METHODS: Comorbidities and comedication use in the 1509 ARAMIS participants treated with darolutamide 600 mg twice daily or placebo were assessed. A population pharmacokinetic analysis evaluated whether comedications affected the pharmacokinetics of darolutamide in a subset of 388 patients. A subgroup analysis of adverse events (AEs) in statin users versus nonusers was conducted. RESULTS: Most participants (median age 74 years) had at least one comorbidity (98.4% in both arms) and used at least one comedication (98.7% with darolutamide vs. 98.0% with placebo); these were similar across study arms. Despite frequent use of comedications with DDI potential, no significant effects on darolutamide pharmacokinetics were identified. Comedications included lipid-modifying agents (34.5%), ß-blockers (29.7%), antithrombotics (42.8%), and systemic antibiotics (26.9%). AE incidence was similar across study arms in statin users and nonusers. Study limitations include the small sample size for sub-analyses. CONCLUSIONS: These analyses suggest the pharmacokinetic profile of darolutamide is not affected by a number of commonly administered drugs in patients with nmCRPC. Although pharmacokinetic data have indicated that darolutamide has the potential to interact with rosuvastatin, used to assess DDI in these studies, this finding did not seem to translate into increased AEs due to statin use in the ARAMIS trial. Clinicaltrials.gov identifier: NCT02200614.

BACKGROUND: Darolutamide is a medicine used to treat men with prostate cancer that has not spread to other parts of the body (nonmetastatic). Often, these patients are taking other medicines for common age-related illnesses. Taking more than one medicine at the same time increases the chances of what is known as drug­drug interactions. Drug­drug interactions can decrease how well the medicines work or may sometimes increase side effects. STUDY AIM: To test for possible drug­drug interactions in men with prostate cancer who take darolutamide alongside other medicines. STUDY PARTICIPANTS: Men with nonmetastatic prostate cancer who were being treated with a medicine that lowers testosterone, a chemical in the body that causes prostate cancer tumors to grow. Participants took two darolutamide 300 mg tablets, or an inactive placebo, twice a day. WHAT DID THE RESEARCHERS MEASURE?: The researchers documented the number of medicines taken by each participant and the number of other medical conditions that they had. Tests were done to find out whether other medicines affected the way that darolutamide works in the body and whether patients taking darolutamide alongside other medicines experienced more side effects. RESULTS: As would be expected, based on the typical age of patients with prostate cancer, more than 90% of participants in this study used medicines other than darolutamide to manage common age-related illnesses or medical conditions. Taking medicines alongside darolutamide did not impact how darolutamide worked in the body and did not increase the number of side effects experienced by patients. Darolutamide is known to interact with rosuvastatin, a cholesterol-lowering drug. However, in this study, there was no overall increase in side effects among darolutamide-treated patients who took this type of drug compared with in those who did not. CONCLUSION: In this study of patients with nonmetastatic prostate cancer, limited drug­drug interactions were seen when taking darolutamide alongside other medicines given to these patients to manage age-related medical conditions.

Formal statistical testing and inference in randomized phase II trials in medical oncology.

OBJECTIVES: With the growing number of new anticancer therapies, randomized phase II trials have been used more often in oncology. Although the primary objective of such trials is not to formally compare results between arms, this practice seems frequent. We sought to quantify the frequency of use of formal statistical testing or inference through the use of P values and confidence intervals (CIs) in randomized phase II trials. METHODS: We searched PubMed for randomized phase II trials assessing systemic cancer therapies published in the years 1995/1996 and 2005/2006. For each study, 2 reviewers independently abstracted data, including reporting of P values and CIs for the primary endpoint. RESULTS: We retrieved 288 articles, 107 of which were eligible for analysis. The median number of patients per trial was 94, the primary endpoint was response rate in 71 (66.4%) cases, and a control arm was present in 55 (51.4%) trials. Either P values or CIs for the primary endpoint were reported in 85 (79.4%; 95% CI, 70.8%-86.1%) cases. Year of publication, source of funding, and use of a control group were not associated with this practice. CONCLUSIONS: Formal statistical comparisons between arms of randomized phase II trials are frequently undertaken in medical oncology. The extent to which such a practice abrogates phase III testing is unknown.

Further evidence of the prognostic role of pretreatment levels of CA 19-9 in advanced pancreatic cancer.

OBJECTIVE: We and others have previously suggested that pretreatment levels of CA 19-9 correlate with overall survival (OS) among patients with advanced pancreatic cancer treated with gemcitabine. We sought to confirm the prognostic role of the pretreatment level of CA 19-9 in patients with advanced pancreatic cancer treated with chemotherapy. METHODS: We retrospectively identified 50 patients with locally advanced or metastatic pancreatic cancer treated in the first-line with single-agent gemcitabine or combinations. Patients could also have received second-line treatment. Kaplan-Meier estimates of OS were compared with the log-rank test, and multivariate analysis was done using the Cox model. RESULTS: Twenty-seven patients were female with a mean age of 64.3 years, and 82% were metastatic upon diagnosis. The median OS for the entire sample was 11 months, and the median CA 19-9 level was 542 U/mL. Significant predictors of OS in univariate analyses were the first-line use of combined chemotherapy (p=0.006) and use of erlotinib in any line (p=0.002), with borderline significance for pretreatment levels of CA 19-9 (p=0.052). In multivariate analysis, only use of erlotinib (p=0.003) and pretreatment CA 19-9 level (p=0.026) were significantly associated with OS. CONCLUSION: Our study lends further support to use of the pre-chemotherapy level of CA 19-9 as a prognostic indicator in clinical practice and as a stratification factor in clinical trials. The association between erlotinib use and OS may have been biased by patient selection, notwithstanding the positive results from a previous randomized trial.

Further evidence of the prognostic role of pretreatment levels of CA 19-9 in advanced pancreatic cancer / Evidência adicional do papel prognóstico do nível pré-tratamento de CA 19-9 em câncer de pâncreas avançado

OBJECTIVE: We and others have previously suggested that pretreatment levels of CA 19-9 correlate with overall survival (OS) among patients with advanced pancreatic cancer treated with gemcitabine. We sought to confirm the prognostic role of the pretreatment level of CA 19-9 in patients with advanced pancreatic cancer treated with chemotherapy. METHODS: We retrospectively identified 50 patients with locally advanced or metastatic pancreatic cancer treated in the first-line with single-agent gemcitabine or combinations. Patients could also have received second-line treatment. Kaplan-Meier estimates of OS were compared with the log-rank test, and multivariate analysis was done using the Cox model. RESULTS: Twenty-seven patients were female with a mean age of 64.3 years, and 82 percent were metastatic upon diagnosis. The median OS for the entire sample was 11 months, and the median CA 19-9 level was 542 U/mL. Significant predictors of OS in univariate analyses were the first-line use of combined chemotherapy (p=0.006) and use of erlotinib in any line (p=0.002), with borderline significance for pretreatment levels of CA 19-9 (p=0.052). In multivariate analysis, only use of erlotinib (p=0.003) and pretreatment CA 19-9 level (p=0.026) were significantly associated with OS. CONCLUSION: Our study lends further support to use of the pre-chemotherapy level of CA 19-9 as a prognostic indicator in clinical practice and as a stratification factor in clinical trials. The association between erlotinib use and OS may have been biased by patient selection, notwithstanding the positive results from a previous randomized trial.

OBJETIVO: Estudos anteriores pelo nosso grupo e por outros autores sugerem que o nível pré-tratamento do marcador tumoral CA 19-9 se correlaciona com a sobrevida global (SG) em pacientes com câncer de pâncreas avançado tratados com gencitabina. Nosso objetivo foi o de confirmar o papel prognóstico do nível pré-tratamento do CA 19-9 em pacientes com câncer de pâncreas avançado tratados com regimes variados de quimioterapia. MÉTODOS: Identificamos retrospectivamente 50 pacientes com câncer de pâncreas localmente avançado ou metastático tratados em primeira linha com gencitabina ou combinações contendo esse agente. Os pacientes poderiam ter recebido ainda tratamento em segunda linha com outros agentes. As estimativas de SG pelo método de Kaplan-Meier foram comparadas pelo teste log-rank, e a análise multivariada foi feita usando-se o modelo de Cox. RESULTADOS: Vinte e sete pacientes eram do sexo feminino, a idade média foi de 64,3 anos, e 82 por cento tinham doença metastática ao diagnóstico. A mediana de SG para a amostra como um todo foi de 11 meses, e o nível mediano de CA 19-9 foi de 542 U/mL. Fatores preditivos de SG em análises univariadas foram o uso de quimioterapia combinada em primeira linha (p=0,006) e o uso de erlotinibe (p=0,002), com nível de significância limítrofe para nível pré-tratamento de CA 19-9 (p=0,052). Na análise multivariada, apenas o uso de erlotinibe (p=0,003) e o nível pré-tratamento de CA 19-9 (p=0,026) estiveram associados com SG de maneira significativa. CONCLUSÃO: Nosso estudo fornece evidência adicional para o uso do nível pré-tratamento de CA 19-9 como indicador prognóstico e como fator de estratificação em ensaios clínicos. A associação entre uso de erlotinibe e SG pode ter sido devida à seleção de pacientes, não obstante o resultado de um estudo randomizado recente mostrando o benefício desse tratamento.

Estudos brasileiros apresentados nos Encontros Anuais da ASCO entre 2001 e 2007: aumento de produção, com baixa taxa de publicação / Brazilian studies presentes at the ASCO Annual Meetings, 2001 throug 2007: increasing output with low publication rates

A pesquisa clínica está crescendo no Brasil, e muitos dos estudos recentes importantes no campo da oncologia incluíram um número substancial de pacientes brasileiros. Entretanto, é difícil estabelecer até que ponto ocorreu um aumento proporcional da pesquisa originada no Brasil. Objetivou-se responder a essa questão através de uma análise bibliométrica de estudos brasileiros apresentados nos Encontros Anuais da American Society of Clinical Oncology(ASCO). Foi realizada uma busca manual dos 24.998 abstracts publicados nos Anais do Encontro da ASCO duranteos anos de 2001 a 2007. Os abstracts definidos como brasileiros foram aqueles em que pelo menos dois terços das instituições eram do Brasil. Foram identificados 244 estudos brasileiros (0,97 por cento do total). Houve um aumentosignificativo da proporção de estudos brasileiros ao longo dos anos compreendidos pelo estudo (P=0,017). Dos 244 estudos, 69,6 por cento não foram apresentados no encontro, aparecendo apenas nos Anais como Publication Only. Depois de um seguimento mediano de 35 meses, apenas 16,9 por cento dos abstracts de 2001 a 2005 foram publicados em revistas indexadas nas bases de dados Medline e Lilacs, com um tempo mediano até a publicação de 13,5 meses. Este estudo demonstra empiricamente o aumento da produção científica por parte dos pesquisadores brasileiros na área de oncologia, mas sugere também que é necessário um esforço para aumentar a taxa de publicação dos estudos.

Magnetic resonance imaging urodynamics. Technique development and preliminary results.

OBJECTIVES: In this preliminary study we report the development of the video urodynamic technique using magnetic resonance imaging (MRI). MATERIALS AND METHODS: We studied 6 women with genuine stress urinary incontinence, diagnosed by history and physical examination. Urodynamic examination was performed on multichannel equipment with the patient in the supine position. Coughing and Valsalva maneuvers were performed at volumes of 150, 250 and 350 mL. Simultaneously, MRI was carried out by using 1.5 T GE Signa CV/i high-speed scanner with real time fluoroscopic imaging possibilities. Fluoroscopic imaging was accomplished in the corresponding planes with T2-weighted single shot fast spin echo sequences at a speed of about 1 frame per second. Both studies were recorded and synchronized, resulting in a single video urodynamic examination. RESULTS: Dynamic MRI with cine-loop reconstruction of 1 image per second demonstrated the movement of all compartment of the relaxed pelvis during straining with the concomitant registration of abdominal and intravesical pressures. In 5 patients, urinary leakage was demonstrated during straining and the Valsalva leak point pressure (VLPP) was determined as the vesical pressure at leak subtracted from baseline bladder pressure. Mean VLPP was 72.6 cm H2O (ranging from 43 to 122 cm H2O). CONCLUSIONS: The concept of MRI video urodynamics is feasible. In a clinical perspective, practical aspects represent a barrier to daily use and it should be recommended for research purposes.

Magnetic resonance imaging urodynamics: technique development and preliminary results

OBJECTIVES: In this preliminary study we report the development of the video urodynamic technique using magnetic resonance imaging (MRI). MATERIALS AND METHODS: We studied 6 women with genuine stress urinary incontinence, diagnosed by history and physical examination. Urodynamic examination was performed on multichannel equipment with the patient in the supine position. Coughing and Valsalva maneuvers were performed at volumes of 150, 250 and 350 mL. Simultaneously, MRI was carried out by using 1.5 T GE Signa CV/i high-speed scanner with real time fluoroscopic imaging possibilities. Fluoroscopic imaging was accomplished in the corresponding planes with T2-weighted single shot fast spin echo sequences at a speed of about 1 frame per second. Both studies were recorded and synchronized, resulting in a single video urodynamic examination. RESULTS: Dynamic MRI with cine-loop reconstruction of 1 image per second demonstrated the movement of all compartment of the relaxed pelvis during straining with the concomitant registration of abdominal and intravesical pressures. In 5 patients, urinary leakage was demonstrated during straining and the Valsalva leak point pressure (VLPP) was determined as the vesical pressure at leak subtracted from baseline bladder pressure. Mean VLPP was 72.6 cm H2O (ranging from 43 to 122 cm H2O). CONCLUSIONS: The concept of MRI video urodynamics is feasible. In a clinical perspective, practical aspects represent a barrier to daily use and it should be recommended for research purposes.