Impact of androgen receptor pathway inhibitor (ARPI) dose reduction on overall survival of metastatic castration-resistant prostate cancer: A multi-centre retrospective study.

Abstract

115 Background: Androgen receptor pathway inhibitors (ARPIs) have been a cornerstone in the management of metastatic castration-resistant prostate cancer (mCRPC) but can be associated with increased risk of cardiovascular disease, fractures and falls, and toxic cognitive effects. Dose reductions are frequently implemented to manage toxicity or minimise drug interactions, but their impact on overall survival (OS) remains unclear. This is a multi-institutional study from 4 UK NHS Foundation Trusts to evaluate the effect of ARPI dose reduction on OS outcomes in patients with mCRPC. Methods: A retrospective cohort study of mCRPC patients treated with ARPIs in the period from 2016-2018. We collected patient demographics; ,Docetaxel in hormone sensitive setting, PSA nadir level after the start of ARPIs, dose reduction and reason for reduction, and date of death or last follow-up up. Median OS calculated from the date of the start of ARPI until the date of death or lost to follow-up. Survival outcomes were assessed using Kaplan-Meier analysis and Cox proportional hazards models, adjusting for age, disease volume, docetaxel use, and PSA level at diagnosis and PSA Nadir. Results: The median age of the cohort was 69.7 years (range: 41–95). Of the 607 patients, 71% received enzalutamide and 29% received abiraterone. High-volume disease was present in 44.2% of patients, and 21.3% received docetaxel. Dose reduction of ARPI occurred in 14.3% of patients (n=87), with fatigue and cardiovascular comorbidities being the most common reasons. Median OS for the whole cohort was 22 months (95% CI: 19.9–24.01). Patients who underwent dose reduction had a significantly longer median OS of 31.0 months (95% CI: 25.2–36.9) compared to 21.0 months (95% CI: 19.0–23.0) in those without dose reduction. Cox regression analysis confirmed that dose reduction was independently associated with improved survival (HR = 0.714, 95% CI: 0.560–0.911, p = 0.007). Conclusions: Though the landscape for therapy options has now changed, with increasing use of ARPI at the time of initial diagnosis of hormone-sensitive metastatic prostate cancer, this retrospective review is hypothesis-generating. Further investigation is warranted as to whether dose reduction of ARPI can improve quality of life, reduce side effects and impacts on OS. These findings further support recruitment to the Cancer Research UK (CRUK) and Prostate Cancer UK (PCUK) -funded ENHANCE study. Multivariate Cox regression of different prognostic factors in relation to overall survival of metastatic castrate resistant prostate cancer. Parameter Sig. Exp(B) 95.0% CI for Exp(B) 95.0% CI for Exp(B) Lower Upper Dose reduction 0.007 0.714 0.560 0.911 Age 0.000 1.038 1.026 1.051 Volume of disease 0.026 1.106 1.012 1.209 Docetaxel in Hormone sensitive setting 0.000 0.814 0.732 0.904 PSA nadir level after start of ARPI 0.000 1.002 1.001 1.002