ASCO 2022: Influence of Darolutamide on Cabazitaxel Systemic Exposure

(UroToday.com) The 2022 ASCO annual meeting featured a session on prostate cancer, including a presentation by Dr. Stefan Buck discussing the influence of darolutamide on cabazitaxel systemic exposure. Taxane efficacy in metastatic castration-resistant prostate cancer (mCRPC) patients is limited due to resistance development. In preclinical models it has been shown that addition of the androgen receptor signaling inhibitor enzalutamide improves cabazitaxel efficacy. However, Dr. Buck and colleagues have previously shown that the clinical utility of this combination is hampered by a strong CYP3A4 drug-drug interaction with enzalutamide, resulting in a 22% reduced cabazitaxel systemic exposure. Darolutamide has much weaker CYP3A4 inducing effects and therefore may affect cabazitaxel systemic exposure to a lesser extent.


This study investigated the influence of darolutamide on cabazitaxel plasma exposure. mCRPC patients were enrolled on cabazitaxel monotherapy (20 mg/m2 every 3 weeks) on day 1 and received concomitant darolutamide (600 mg twice daily) from day 2 onwards for maximal 12 weeks. During cabazitaxel infusion on day 1, and after 6 and 12 weeks of darolutamide treatment, cabazitaxel systemic exposure was measured via Area Under the Curve from 0 to 24 hours (AUC0-24h).

Cabazitaxel systemic exposure in 18 patients after 6 weeks of darolutamide was not significantly different compared to prior to darolutamide treatment (AUC0-24h: -4%; 95%CI -19 – +13%; p = 0.58): 

CYP3A4-0.jpg

Also, after 12 weeks of darolutamide treatment, cabazitaxel systemic exposure was unaltered (AUC0-24h: +4%; 95%CI -10 – +20%; p = 0.54). Darolutamide plasma concentrations were constant throughout the study as highlighted in the following table:

CYP3A4-1.jpg

Dr. Buck concluded this presentation discussing the influence of darolutamide on cabazitaxel systemic exposure with the following take-home messages:

  • From a pharmacokinetic perspective cabazitaxel and darolutamide can be safely combined in mCRPC patients
  • These findings pave the way for testing the efficacy of this promising combination in an era of combination regimens for prostate cancer
  • Future directions include a randomized phase 2 study assessing cabazitaxel +/- darolutamide in patients previously treated with a novel androgen receptor signaling agent

Presented by: Stefan Buck, Erasmus MC Cancer Institute, Rotterdam, Netherlands

Written by: Zachary Klaassen, MD, MSc – Urologic Oncologist, Assistant Professor of Urology, Georgia Cancer Center, Augusta University/Medical College of Georgia, @zklaassen_md on Twitter during the 2022 American Society of Clinical Oncology (ASCO) Annual Meeting, Chicago, IL, Fri, June 3 – Mon, June 7, 2022.