Pharmacokinetic profile of fulvestrant 500 mg vs 250 mg: Results from the NEWEST study

Abstract

579 Background: Neoadjuvant Endocrine Therapy for Women with Estrogen-Sensitive Tumors (NEWEST) is a randomized, phase II study comparing fulvestrant approved dose (AD; 250 mg/month) with a high-dose regimen (HD; 500 mg/month plus 500 mg on Day 14 of Month 1) as neoadjuvant therapy for postmenopausal women with newly diagnosed, estrogen receptor (ER)-positive, locally advanced breast cancer. In the primary analysis, fulvestrant HD compared with AD resulted in a statistically significant greater reduction in Ki67 labeling index (LI) as well as greater downregulation of both ER and progesterone receptor (PgR) expression. Here we report pharmacokinetic (PK) data from NEWEST. Methods: Core biopsies were taken at baseline, Wk 4 and at surgery (Wk 16), and assessed for changes in Ki67 LI, ER, and PgR expression (ER and PgR Intensity Score analyzed using ChromaVision™ Automated Cellular Imaging System). Blood samples for PK analysis were taken on Days 0, 28, 56, 84, and 112. An additional sample was taken between Days 6–10 (both groups) and Days 20–24 (HD group only). HPLC-MS and liquid-liquid extraction were used to determine plasma fulvestrant levels. Plasma samples were analyzed using NONMEM, and Bayesian PK parameter estimates were used to determine Cmax and AUC0–28 days at Wks 4 and 16. Correlations between fulvestrant plasma levels, magnitude of biomarker (Ki67 LI, ER, and PgR) downregulation, and clinical activity were also assessed. Results: A total of 208 women were included in the PK analyses. Fulvestrant plasma levels and exposure were greater in the HD arm than the AD arm at Wks 4 and 16 (Wk 4: Cmax HD 24.5 ± 6.9 vs AD 8.8 ± 1.7 ng/mL; AUC0–28 days HD 12804 ± 3550 vs AD 4005 ± 840 ng.h/mL). Increased total monthly fulvestrant exposure correlated with increased downregulation of Ki67 LI, ER and PgR. Detailed modeling of the endpoints suggested a non-linear decrease in both Ki67 and PgR to a plateau of approximately 20–30% of the baseline values. ER levels were downregulated to approximately 50% of the pretreatment values. Conclusions: Increased fulvestrant exposure correlates with increased downregulation of Ki67 LI, ER and PgR. The relationship between drug levels and clinical response will be presented. Fulvestrant HD is currently being investigated in the metastatic disease setting. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration AstraZeneca AstraZeneca AstraZeneca AstraZeneca AstraZeneca AstraZeneca AstraZeneca