Exposure–response analyses of abiraterone and its metabolites in real-world patients with metastatic castration-resistant prostate cancer

Abstract

Background Abiraterone acetate is an oral 17α-hydroxylase/C17,20-lyase (CYP17) inhibitor approved for the treatment of metastatic castration-resistant prostate cancer (mCPRC) patients. Previously, a prospective observational trial demonstrated a relationship between abiraterone trough concentrations (C min ) in plasma and treatment efficacy. The aim of our study was to investigate the exposure-response relationship of abiraterone and its metabolites, and to study if the proposed target for abiraterone of 8.4 ng/mL is feasible in a "real-world" patient cohort. Patients and methods mCRPC patients who had at least one abiraterone plasma concentration at steady-state were included in this study. Plasma abiraterone and its metabolites levels were analyzed using a validated liquid chromatography-mass spectrometry method. Using calculated C min values of abiraterone and its active metabolite Δ(4)-abiraterone (D4A), univariate, and multivariable Cox regression analyses were performed. Results Sixty-two patients were included in this retrospective analysis, of which 42% were underexposed (mean abiraterone C min ≤ 8.4 ng/mL). In multivariable analysis, C min ≥ 8.4 ng/mL was associated with longer prostate-specific antigen (PSA) independent progression-free survival (16.9 vs 6.1 months; p = 0.033), which resulted in a hazard ratio of 0.44 (95% confidence interval: 0.23-0.82, p = 0.01). D4A C min did not show a relationship with treatment efficacy. Conclusion Our study shows that mCRPC patients with an abiraterone C min ≥ 8.4 ng/mL have a better prognosis compared with patients with low C min . Monitoring C min of abiraterone can help to identify those patients at risk of suboptimal treatment for whom treatment optimization may be appropriate.

Therapeutic drug monitoring of oral targeted antineoplastic drugs

“…This threshold was later confirmed in a real-world patient cohort (n = 62, PFS 6.1 vs. 16.9 months, p = 0.033) [63]. Yet, at the standard dose of 1000 mg once daily (QD), 35% and 42% of patients, respectively, did not reach this target [62,63]. A prospective study (n = 32) demonstrated that 20 patients (63%) had at least one C min < 8.4 ng/mL with standard care [40]; however, when a light meal or snack was concomitantly taken with abiraterone, adequate exposure in 28 patients (87.5%) without additional toxicities was achieved [40].…”

“…In an observational study in 61 metastatic castration-resistant prostate cancer patients, C min ≥ 8.4 ng/mL were associated with a significantly longer PFS compared to C min < 8.4 ng/ mL (PFS 7.4 vs 12.2 months, p = 0.044) [62]. This threshold was later confirmed in a real-world patient cohort (n = 62, PFS 6.1 vs. 16.9 months, p = 0.033) [63]. Yet, at the standard dose of 1000 mg once daily (QD), 35% and 42% of patients, respectively, did not reach this target [62,63].…”

Liquid biopsy reveals KLK3 mRNA as a prognostic marker for progression free survival in patients with metastatic castration‐resistant prostate cancer undergoing first‐line abiraterone acetate and prednisone treatment

“…Next to the biomarkers, we studied the effect of drug exposure on PFS. It has been suggested that underexposure of abiraterone ( C trough level < 8.4 ng·mL −1 ) is related to shorter PFS [26,27]. The beneficial effect of higher abiraterone exposure levels could not be confirmed in this study for chemotherapy naïve patients treated with AA‐P.…”

The effect of chemotherapy on the exposure–response relation of abiraterone in metastatic castration‐resistant prostate cancer

“…Nuland et al confirmed the exposure threshold in a real-life cohort of 62 mCRPC patients, in which 42% of the patients were chemotherapy-pretreated. Suprisingly, in the group of patients with an exposure below the threshold 65% of the patients were chemotherapy-pretreated versus 25% in the group of patients with an exposure above the threshold 9 . So it might be well possible that if both studies analysed the patients who received AA before or after chemotherapy in mCRPC setting independently, results would be consistent with our findings.…”

“…It was demonstrated that patients with primary resistance to AA had a significantly lower abiraterone exposure, compared to responders 8 . Furthermore, earlier studies in patients with mCRPC treated with AA showed that patients exposed to an abiraterone trough concentration (Cmin) above 8.4 ng/mL had an improved progression-free survival (PFS) compared to patients below this threshold 7,9 . This exposure threshold was thereafter proposed for all mCRPC patients treated with AA.…”