Open-label phase II clinical trial of ketoconazole as CYP17 inhibitor in metastatic or advanced non-resectable granulosa cell ovarian tumors: the GREKO (GRanulosa Et KetOconazole) trial, GETHI 2011-03.

BACKGROUND: Granulosa cell ovarian tumor (GCT) is characterized by a pathognomonic mutation in the FOXL2 gene (402 C > G) that leads to an overactivation of steroidogenesis. CYP17 is a key enzyme in such process and can be inhibited by ketoconazole. METHODS: We designed a phase II clinical trial to assess the efficacy of ketoconazole in advanced GCT and conducted several in vitro studies to support the clinical findings. RESULTS: From October 1st 2012 to January 31st 2014, six evaluable patients were recruited in ten hospitals of the Spanish Group for Transversal Oncology and Research in Orphan and Infrequent Tumors" (GETTHI). FOXL2 (402C > G) mutation was confirmed in three; two cases were wild type and it could not be assessed in one. No objective response by RECIST was observed, but five cases achieved stable disease longer than 12 months. Median progression-free survival was 14.06 months (CI 95% 5.43-22.69) for the whole study population (3.38 and 13.47 months for wild-type cases and 14.06, 20.67 and 26.51 for those with confirmed FOXL2 mutation). Median overall survival was 22·99 months (CI 95% 8.99-36.99). In vitro assays confirmed the activity of ketoconazole in this tumor and suggested potential synergisms with other hormone therapies. CONCLUSION: Ketoconazole has shown activity in advanced GCT in clinical and in vitro studies. Based on these data, an orphan designation was granted by the European Medicines Agency for ketoconazole in GCT (EU/3/17/1857). GOV IDENTIFIER: NCT01584297.

Relación entre la terapia hormonal en cáncer de próstata avanzado e incidencia del síndrome metabólico y eventos cardiovasculares: Estudio prospectivo en el Hospital San Borja Arriarán (HSBA) / Relationship between hormonal therapy in advanced prostate cancer and incidence of metabolic syndrome and cardiovascular events: Prospective study at the San Borja Arriarán Hospital (HSBA)

La terapia hormonal con deprivación de andrógenos constituye un pilar fundamental en el manejo del cáncer de próstata avanzado y metastásico, sin embargo, se han descrito diversos efectos adversos. Dentro de ellos, los de mayor relevancia por su morbimortalidad asociada, son el desarrollo del síndrome metabólico y eventos cardiovasculares. En Latinoamérica no existen estudios prospectivos que evalúen esta relación. MATERIALES Y MÉTODOS: Se diseñó un estudio prospectivo. Se seleccionaron 87 pacientes del HSBA con diagnóstico de cáncer de próstata avanzado o metastásico, que iniciaron terapia hormonal entre abril de 2016 y abril de 2017. Se registraron datos clínicos: Presión Arterial, Circunferencia abdominal, Índice de Masa Corporal; y datos de laboratorio: Colesterol total, HDL, LDL, Glicemia en Ayunas, Insulinemia Basal y Testosterona Total. El registro de datos fue al inicio y a los 6 meses de iniciada la hormonoterapia. Para el análisis estadístico de las variables registradas se utilizó el test t de Student y Wilcoxon según la distribución de las variables, con una significancia estadística de p<0.05 y el programa SPSS 22.0. Se contó con el consentimiento informado de cada paciente y aprobación del comité de ética. RESULTADOS: El promedio de edad de los pacientes evaluados fue de 74.3 años. De los 87 pacientes, un total de 67 presentaron antecedentes de factores de riesgo cardiovascular (FRCV); 42 era sólo hipertensos, 4 eran sólo diabéticos, y 42 presentaban ambas patologías. De las variables a evaluar, no se evidenciaron diferencias significativas en parámetros clínicos ni de laboratorio en los distintos tiempos. Ningún paciente en el período de estudio desarrolló algún evento cardiovascular. DISCUSIÓN: Se realizó un estudio prospectivo en pacientes con cáncer de próstata del HSBA que recibieron terapia hormonal. Se evaluó la incidencia del síndrome metabólico, tanto en parámetros clínicos y de laboratorio. En nuestra serie no encontramos un aumento estadísticamente significativo en la incidencia de síndrome metabólico, resultado acorde con un estudio retrospectivo realizado en nuestro centro. Por otro lado, estudios internacionales europeos y norteamericanos notifican que la hormonoterapia sí produce aumento en la incidencia del síndrome metabólico y con ello, aumento del riesgo de eventos cardiovasculares. Hacen falta más estudios de tipo prospectivos y de mayor seguimiento para poder confirmar nuestra hipótesis. (AU)

INTRODUCTION: Androgen deprivation therapy is a fundamental pillar in the management of advanced and metastatic prostate cancer, however, several adverse effects have been described. Among them, the most relevant for their associated morbidity and mortality are the development of metabolic syndrome and cardiovascular events. In Latin America there are no prospective studies that evaluate this relationship. METHODOLOGY: A prospective study was designed. A total of 87 HSBA patients with diagnosis of advanced or metastatic prostate cancer were selected, who initiated hormonal therapy between April 2016 and April 2017. Clinical data were recorded: Blood Pressure, Abdominal Circumference, Body Mass Index; and laboratory data: Total cholesterol, HDL, LDL, glycemia, basal insulinemic and Total Testosterone. Data recording was at the beginning and at 6 months after the start of therapy. For the statistical analysis the Student t test and Wilcoxon were used according to the distribution of the variables, with a statistical significance of p <0.05 and with the software SPSS 22.0. We had the informed consent of each patient and approval of the ethics committee. RESULTS: The average age of the patients evaluated was 74.3 years. Of the 87 patients, a total of 67 had a history of cardiovascular risk factors (CVRF); 42 was only hypertensive, 4 were diabetic only, and 42 had both pathologies. Of the variables to be evaluated, there were no significant differences in clinical or laboratory parameters at different times. No patient in the study period developed any cardiovascular event. DISCUSSION: A prospective study was conducted in patients with prostate cancer of HSBA who received hormonal therapy. The incidence of metabolic syndrome was evaluated, both in clinical and laboratory parameters. In our series, we did not find a statistically significant increase in the incidence of metabolic syndrome, a result consistent with a retrospective study conducted in our center. On the other hand, European and North American international studies report that hormone therapy does produce an increase in the incidence of the metabolic syndrome and with it, an increased risk of cardiovascular events. More prospective and longer follow-up studies are needed to confirm our hypothesis (AU)