RESUMO
BACKGROUND AND OBJECTIVE: Olaparib + abiraterone has a combined antitumor effect in metastatic castration-resistant prostate cancer (mCRPC), but the efficacy of this combination in patients with DNA damage repair (DDR)-deficient mCRPC progressing after abiraterone is unknown. Our aim was to compare the efficacy of olaparib + abiraterone versus olaparib monotherapy for patients with DDR-deficient mCRPC progressing after abiraterone. METHODS: The study included 86 consecutive patients with DDR-deficient mCRPC progressing after abiraterone: 34 received olaparib + abiraterone, and 52 received olaparib monotherapy. DDR-deficient status was defined as the presence of a DDR gene with a pathogenic or likely pathogenic variant (DDR-PV), or with a variant of unknown significance (DDR-VUS). We assessed progression-free survival (PFS) and overall survival (OS) using the Kaplan-Meier method. Potential factors influencing PFS and OS were compared between the treatment arms using Cox proportional-hazards models. The prostate-specific antigen (PSA) response, the treatment effect across subgroups, and adverse events (AEs) were also evaluated. KEY FINDINGS AND LIMITATIONS: Median follow-up was 9 mo. In the overall cohort, median PFS and OS were significantly longer in the combination arm than in the monotherapy arm (PFS: 6.0 vs 3.0 mo; hazard ratio [HR] 0.41, 95% confidence interval [CI] 0.25-0.67; p < 0.01; OS: 25.0 vs 12.0 mo; HR 0.30, 95% CI 0.14-0.67; p < 0.01). PSA responses were significantly higher following combination therapy versus monotherapy. Combination therapy had significantly better efficacy in the DDR-PV and DDR-VUS subgroups, and was an independent predictor of better PFS and OS. AE rates were acceptable. The retrospective nature, small sample size, and short follow-up are limitations. CONCLUSIONS: Olaparib + abiraterone resulted in better PFS and OS than olaparib alone for patients with DDR-deficient mCRPC progressing after abiraterone. These results need to be confirmed by a large-scale prospective randomized controlled trial. PATIENT SUMMARY: Our study shows that the drug combination of olaparib plus abiraterone improved survival over abiraterone alone for patients who have mutations in genes affecting DNA repair and metastatic prostate cancer resistant to hormone therapy. The results provide evidence of a synergistic effect of the two drugs in these patients.
RESUMO
Anisodamine exerts significant protective effect on ischemia/reperfusion (I/R) injury in various organs. However, little is known about the mechanisms of anisodamine in renal I/R injury. Activation of extracellular regulated protein kinases (ERK) pathway promotes the repair of renal epithelial cells following oxidant injury. The present study investigated whether the renoprotective role of anisodamine against renal I/R injury in rats was associated with the activation of ERK signaling pathway. Male Sprague-Dawley (SD) rats were separated into the following groups: Sham-operated group, I/R group, anisodamine-treated group, PD98059 (MEK-1/ERK inhibitor)-treated group and anisodamine plus PD98059-treated group. A rat model of renal I/R was established by excising the right kidney and then clamping the left renal pedicle for 45 min followed by reperfusion for 24 h. Serum and renal tissue samples were obtained for assays of the associated morphological, molecular and biochemical parameters. Treatment with anisodamine ameliorated renal I/R injury, as evidenced by improvements of renal histology and kidney function, a decrease in paller's score and apoptosis index. Anisodamine also upregulated the phosphorylation levels of ERK1/2 and its downstream targets, including 90 ribosomal S6 kinase (p90rsk) and Bad, as well as the expression of antiapoptotic Bcl-2 protein, downregulated the expression levels of proapoptotic proteins Bax and cleaved-caspase-3, whereas these effects were greatly abolished by administration of PD98059. In conclusion, the results suggest that anisodamine prevents renal I/R injury in rats as a result of an activation of the ERK signaling pathway and anti-apoptotic properties.