RESUMO
INTRODUCTION: Several small studies have reviewed the efficacy of abiraterone acetate plus prednisolone (AAP) in clinical practice outside a trial setting. We report the largest cohort study of clinical outcomes in metastatic castrate-resistant prostate cancer (mCRPC) patients treated with AAP in a multicenter multiracial clinical setting. METHODS: A retrospective analysis on mCRPC patients treated at four tertiary hospitals in Singapore from 2012 to 2017 was conducted. Disease characteristics, treatment outcomes, and adverse events were retrieved from electronic medical records. Primary clinical end-point was overall survival (OS). A subset analysis of patients with various variables and OS curves were generated using the Kaplan-Meier method and compared using the log-rank test. RESULTS: Out of 200 patients with mCRPC treated with AAP, 163 (81.5%) patients were chemo-naïve (CN) and 37 (18.5%) patients were postchemotherapy (PC), with the median age of 68 (34-87) and 65 (52-80) years, respectively. Median OS was 20.0 (95% CI, 18.3-22.9) and 10.5 months (95% CI, 1.1-40.5) for CN and PC cohorts, respectively. A subset analysis of 108 patients showed a significantly longer OS in patients who had prior ADT for more than 12 months in CN patients (P < 0.001). Incidences of G3/G4 events were around 6.6%; most common side effect being hypertension with an incidence of 2.4%. CONCLUSIONS: Treatment of CN and PC patients with AAP was associated with a comparable OS and progression-free survival to the reported series. Patients who were responsive to prior ADT of 12 months or more were associated with an improved OS.
Assuntos
Acetato de Abiraterona/uso terapêutico , Anti-Inflamatórios/uso terapêutico , Prednisona/uso terapêutico , Neoplasias de Próstata Resistentes à Castração/mortalidade , Adulto , Idoso , Idoso de 80 Anos ou mais , Quimioterapia Combinada , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico , Neoplasias de Próstata Resistentes à Castração/tratamento farmacológico , Neoplasias de Próstata Resistentes à Castração/patologia , Estudos Retrospectivos , Singapura , Taxa de SobrevidaRESUMO
The ability of aurones to modulate the efflux activities of ABCG2 and ABCB1 was investigated by quantifying their effects on the accumulation of pheophorbideâ A (PhA) in ABCG2-overexpressing MDA-MB-231/R cells and calceinâ AM in ABCB1-overexpressing MDCKII/MDR1 cells. Key structural features for interactions at both ABCG2 and ABCB1 are a methoxylated ringâ A, an intact exocyclic double bond, and the location of the carbonyl bond on ringâ C. Modifications on ringsâ B and C were less critical and served primarily to moderate activity and selectivity for one or both transporters. These SAR trends were quantified by Free-Wilson analyses and are reflected in a pharmacophore model for PhA accumulation. Several compounds were found to be equipotent with fumitremorginâ C (FTC) in promoting PhA accumulation, and they also demonstrated strong affinities for ABCB1. These compounds were disubstituted on ringâ B with methoxy or a combination of methoxy and hydroxy groups. Taken together, our findings highlight the versatility of the aurone template as a lead scaffold for the design of dual-targeting ABCG2 and ABCB1 modulators.