To assess whether the exposure-response relation for abiraterone is different in pre-chemotherapy patients compared to post-chemotherapy patients with metastatic castration-resistant prostate cancer (mCRPC).
Data were collected from three clinical studies in mCRPC patients treated with abiraterone acetate. Cox regression analysis was used to determine the relation between abiraterone exposure and survival (progression-free survival (PFS) and overall survival (OS)). An interaction-term was used to test whether chemotherapy pretreatment was an effect modifier. To investigate the effect of the previously defined exposure threshold of 8.4 ng/mL on survival, Kaplan-Meier analysis was used.
In total 98 mCRPC patients were included, of which 78 were pre-chemotherapy and 20 were post-chemotherapy patients. Chemotherapy pretreatment in mCRPC setting appears to be an effect-modifier. In pre-chemotherapy patients, no significant association between abiraterone exposure and survival was observed (HR 0.68 [95% CI 0.42-1.10], p = 0.12 and HR 0.85 [95% CI 0.46-1.60], p = 0.61, PFS and OS respectively) and no longer survival was seen for patients with an abiraterone exposure above the predefined threshold. In contrast, a significant association was seen in post-chemotherapy patients (HR 0.30 [95% CI 0.12-0.74], p = 0.01 and HR 0.38 [95% CI 0.18-0.82] p = 0.01, PFS and OS respectively), with an increased survival when exposed above this threshold.
Chemotherapy pretreatment in mCRPC setting modifies the abiraterone exposure-response relation. No relation between abiraterone exposure and survival was seen for pre-chemotherapy patients. Therefore, potentially lower doses can be used in this setting to prevent overtreatment and reduce financial toxicity.
British journal of clinical pharmacology. 2021 Aug 26 [Epub ahead of print]
Emmy Boerrigter, Guillemette E Benoist, Joanneke K Overbeek, Rogier Donders, Niven Mehra, Inge M van Oort, Rob Ter Heine, Nielka P van Erp
Department of Pharmacy, Radboud university medical center, Radboud Institute for Health Sciences, Nijmegen, The Netherlands., Department for Heath Evidence, Radboud university medical center, Nijmegen, The Netherlands., Department of Medical Oncology, Radboud university medical center, Nijmegen, The Netherlands., Department of Urology, Radboud university medical center, Radboud Institute for Molecular Life Sciences, Nijmegen, The Netherlands.