Docetaxel for castrate-resistant prostate cancer: the effect of hepatic impairment at the start of therapy on the incidence of adverse events.

Abstract

Introduction Metastasized castration-resistant prostate cancer (mCRPC) is a common type of cancer in European and United States men. Docetaxel (75 mg/m2 as a 60-minute infusion once every 21 days (Q3W)) is a potential treatment option for mCRPC. Docetaxel is metabolized by cytochrome P450 3A4 (CYP3A4) in the liver. The aim of this study is to analyze whether elevated liver parameters at start of docetaxel treatment for patients with mCRPC increases the odds of developing hematological adverse events. With these data we hope to provide clearer guidance on dose reduction.

Method The current study is a retrospective, single-center follow-up study. The study population comprised patients treated at the University Medical Centre Utrecht (UMCU, Utrecht, The Netherlands) with docetaxel for prostate cancer between January 2011 and May 2021. Inclusion criteria: male patients older than 18 years, who were treated conform protocol with docetaxel 75 mg/m2 (Q3W), with a 100% starting dose and known baseline ASAT, ALAT, and AP parameters. Patients with elevated liver parameters (ASAT and/or ALAT >1x ULN concomitant with AP >1x ULN) were assigned to group 2. Patients that did not meet the requirements for elevated liver parameters were assigned to group 1. Primary endpoint of this study was to analyze difference in occurrence of and time until grade 3 or 4 neutropenia or thrombocytopenia or grade 2 or 3 anemia based on the NCI Common Terminology Criteria for Adverse Events Version 5 between both groups.

Results 71 patients were eligible for analysis. 55 patients were assigned to group 1 and 16 to group 2. For grade 3 or 4 neutropenia and thrombocytopenia no significant differences were found in incidence and time until adverse events. Grade 2 or 3 anemia occurred 9 times (56%) in group 2 and 8 times (15%) in group 1. The relative risk (RR) was 3.87 with 95% CI 1.79 – 8.37 (p < 0.001). Time until adverse event in group 1 was 80 days (SD= 58 days) and in group 2 65 days (standard deviation = 47 days)(log rank test; p < 0.0001).

Conclusion Patients with increased liver parameters at start of treatment did not show more grade 3 or 4 neutropenia and thrombocytopenia during treatment compared to patients with normal liver function. Based on these results we conclude that there is no direct need for docetaxel dose reductions for patients with mCRPC based on ASAT or ALAT >1x upper limit of institutional normal (ULN) concomitant with AP >1x ULN.