DN has shown superiority in delaying skeletal related events when given q4w over zoledronic (ZA) acid given q4w. Newer data have shown that ZA given q12w is non-inferior to ZA q4w. The primary endpoint of REDUSE is to show non-inferiority for DN q12w versus q4w (SSE). Here we present the data for the secondary endpoint hypocalcemia (HC).
Patients with metastatic breast cancer (BC) or metastatic castration resistant prostate cancer (PC) (planned N = 1380) were randomized 1:1 to receive DN q4w (Arm A) versus q12w (Arm B) after a 3-month induction phase with application q4w. All patients received vitamin D 400 U (ViD) and calcium (Ca) 500 mg daily. Measurement of serum-calcium was mandatory before each DN injection. This safety interim analysis was performed after 3.5 years of accrual. (N = 634; BC N = 351, PC N = 283).
Patients who received at least 1 dose of DN were considered evaluable. HC was the most common side effect with 23.7% overall (BC 18.6%, PC 30.2%). While HC occurred in 31.6% in Arm A, the rate was 15.8% in Arm B. Grade 3/4 HC was rare (overall: 1.3%, all with PC). After 1 year of treatment, the incidence of HC was lower in both arms (A: 27.2%, B: 14.3%). Since HC improved in more patients in Arm B than Arm A whereas it got worse in Arm A compared to Arm B, a remarkable difference for HC was noticed between the two arms (Table).Table: 1703P
|Change in HC grade after week 16 in patients with HC during induction treatment (196/634) (week 1 – 12: DN q4w Arm A+B, thereafter q4w Arm A, q12w Arm B)||Arm A (N = 106)||Arm B (N = 90)|
|n (%)||n (%)|
|Worsening||48 (45.3%)||23 (25.6%)|
|Stable||29 (27.4%)||15 (16.7%)|
|Improving||29 (27.4%)||52 (57.8%)|
Arm A: Denosumab q4w, Arm B: Denosumab q12w.
In our trial up to 30% of all patients treated with DN experienced HC in the q4w induction phase despite mandatory supplementation and measurement of ViD and Ca. This rate was considerably higher than reported in the registration trials of DN (PC 13.0%, BC 5.5%). After randomization the appearance of HC is remarkably lower in the q12w arm compared to q4w. This suggests that DN given q12w has a more favorable long time toxicity profile (HC) compared to DN q4w.
Clinical trial identification
Legal entity responsible for the study
Swiss Group for Clinical Cancer Research (SAKK).
Swiss State Secretariat for Education, Research and Innovation (SERI) and Santésuisse.
R. von Moos: Advisory board: Amgen, Novartis, Roche. S. Gillessen: Compensated consultancy and advisory roles (including IDMC): AAA International, Active Biotech, Astellas Pharma, Bayer, Bristol-Myers Squibb, CellSearch (Menarini Silicon Biosystems), Clovis, Curevac, Dendreon, Ferring, Innocrin, Janssen, MaxiVAX SA, Millennium, Novartis, Orion, Pfizer, Roche, Sanofi Aventis; Speakers Bureaus (compensated): Janssen, Novartis; Patent application for a biomarker method (WO 2009138392 A1). All other authors have declared no conflicts of interest.