PhD defence S.A.J. (Stefan) Buck

Brief summary:

Taxane chemotherapy is widely used in patients with metastatic prostate cancer. After disease progression on docetaxel, patients with metastatic castration-resistant prostate cancer are eligible for treatment with cabazitaxel. Early resistance to or severe toxicity by taxane chemotherapy, as often observed in clinical practice, demands for novel approaches to prolong initial treatment response.

Further elaborating on preclinical evidence that continued androgen receptor (AR) signaling impairs taxane efficacy in prostate cancer, we demonstrated that the AR signaling inhibitor (ARSi) darolutamide augmented docetaxel efficacy, even in preclinical models progressive on ARSi. In agreement with the role of the AR as a key regulator of the G1-S cell cycle checkpoint, a reduction of tumor cells entering the S-phase upon incubation with the combination was demonstrated. A potential hazard of combination therapies is the provocation of drug-drug interactions that could affect treatment efficacy. In vivo studies revealed no influence of darolutamide on Oatp1b function, an uptake transporter of docetaxel. Cabazitaxel systemic concentrations in patients were not altered when combined with darolutamide. These findings support that combined treatment of a taxane and darolutamide is safe from a pharmacokinetic perspective. 

As taxanes frequently cause severe neutropenia, a population pharmacokinetic-pharmacodynamic model was described to directly link patient characteristics and cabazitaxel systemic exposure to absolute neutrophil count. Cabazitaxel plasma concentrations were found to be predictive of severe neutropenia, enabling early identification of patients at risk for severe neutropenia. In conclusion, novel strategies to prolong response to taxane treatment in metastatic prostate cancer were described in this thesis. Future research will address the clinical implementation of the findings presented in this thesis.