Effect of cathepsin k inhibition on suppression of bone resorption in women with breast cancer and established bone metastases in a 4-week, double-blind, randomized controlled trial

Abstract

1023 Background: In breast cancer patients with metastatic bone disease (MBD), osteolysis releases factors that sustain tumor cell survival and proliferation. Cathepsin (Cat) K inhibition suppresses osteolysis in preclinical models of MBD. The current study assessed the safety and efficacy of odanacatib, a selective Cat K inhibitor, in reducing markers of bone remodeling in women with breast cancer and MBD. Methods: This double-blind study randomized women with breast cancer and MBD to oral odanacatib 5 mg daily for 4 weeks or IV zoledronic acid (ZA) 4 mg given once at study initiation. Bone remodeling was assessed by measuring urinary N-telopeptide of type I collagen corrected for creatinine (uNTx; primary objective, pmol BCE/μmol creatinine); urinary deoxypyridinoline corrected for creatinine (uDPD, pmol/μmol creatinine), and bone formation (serum bone-specific alkaline phosphatase [sBSAP, ng/mL]). Inhibition of Cat K activity was determined by serum crosslinked C-terminal peptide of type I collagen (s1CTP, μg/L). Adverse events (AE) were monitored throughout the 4-week study and up to 14 days after last dose. Results: 43 patients (mean age 60 yrs) received odanacatib (n=29) or ZA (n=14); 40 patients completed 4 weeks. 12 (41%) and 17 (59%) patients on odanacatib and 6 (43%) and 7 (50%) patients on ZA received chemotherapy or hormone therapy, respectively. Results for markers of bone remodeling and Cat K activity are tabulated (Table). The most common AEs were nausea, vomiting, headache, and bone pain, which were generally not attributed to study drug. Conclusions: In women with breast cancer and MBD, the Cat K inhibitor odanacatib suppressed markers of bone resorption after 4 weeks of treatment. Mean uNTx and uDPD were decreased in both treatment groups. The increase in s1CTP suggests specific inhibition of Cat K. In this study, odanacatib was generally safe and well tolerated. Changes from Baseline at Week 4 in Biochemical Markers of Bone Resorption Marker Odanacatib 5 mg (once daily) Zoledronic Acid 4 mg (single dose) Baseline Wk 4 % Change 95% CI Baseline Wk 4 % Change 95% CI uNTx 140 48 -77 -82, -71 175 61 -73 -80, -62 uDPD 18 13 -30 -43, -15 25 15 -52 -64, -36 sBSAP 27 25 -9 -17, -2 36 32 -2 -13, +9 s-1CTP 10 20 +93 +70, +119 10 10 0 -16, +19 Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Merck & Co., Inc Merck & Co., Inc