NCT02229916 (Clinicaltrials.gov).

139 Background: DN given q4w has shown superiority in delaying skeletal related events over q4w zoledronic acid (ZA). Recently it has been demonstrated that ZA q12w is non-inferior to ZA q4w. The objective of REDUSE is to show non-inferiority for DN q12w versus q4w in terms of SSE. Here we present an interim analysis for the secondary endpoint HC. Methods: Patients (pts) with castration resistant prostate cancer (planned N=690) were randomized 1:1 to DN q4w (Arm A) vs q12w (Arm B) after a 16 week induction phase with application q4w. All pts received vitamin D (ViD) 400 U and calcium (Ca) 500 mg daily. Measurement of corrected serum-Ca was mandatory before each DN injection. This interim analysis was performed after 3.5 years of accrual. Men who received ≥ 1 dose of DN were considered evaluable. Results: 383 pts were evaluable. HC occurred in 28.7% during the first 16 weeks (DN q4w for all pts) and 30.2% afterwards. After the induction phase HC occurred in 40.2% in Arm A and in 20.3% in Arm B. Grade 3 (2.1%) and 4 (1.1%) HC were rare, most frequently occurring in the first 16 weeks. After 1 year of treatment, the incidence of HC was lower in both arms (A: 30.8%, B: 18.7%). A clinically relevant difference for HC was noted between the two arms after the induction phase (table). Conclusions: In our trial nearly 30% of all men treated with DN experienced HC in the q4w induction phase despite mandatory supplementation of calcium and ViD and measurement of Ca. This rate was considerably higher than reported in the registration trials of DN (13%). After induction treatment the incidence of HC is considerably 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. Change in HC grade after week 16 (week 1 – 12: DN q4w Arm A+B), thereafter q4w in Arm A and q12w in Arm B. Clinical trial information: NCT02051218. [Table: see text]

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Background Monthly Denosumab (DN) has shown superiority over zoledronic acid (ZA) in delaying skeletal related events. Randomized trials have shown that ZA given every 12 weeks (q12w) is non-inferior to ZA given every 4 weeks (q4w). The primary endpoint of the REDUSE-trial is non-inferiority for SSE for DN q12w versus q4w. Here we present early data for hypocalcemia (HC), a secondary endpoint. Methods Patients with bone metastasis from breast cancer (BC) not pretreated with DN or Bisphosphonates were randomized 1:1 to receive DN q4w (Arm A) versus q12w (Arm B) after a 3-month induction phase with q4w therapy for both arms. All patients received vitamin D 400 U (VitD) and calcium (Ca) 500 mg daily. Measurement of albumin-corrected serum-Ca was mandatory before each DN injection (HC defined as <2.0 mmol/l like in CTCAE V4.0). This safety interim analysis was performed after 3.5 years of accrual. Patients who received at least 1 dose of DN were considered evaluable. Results 351 BC-patients are currently included (177 in Arm A, 174 in Arm B). HC was the most common side effect with a rate of 20% in the first 16 weeks (during the induction phase with DN q4w for both Arms) and 19% afterwards (combined for Arms A and B). After week 16 HC-prevalence differed between the two arms: while HC was present in 25% in Arm A (q4w), the rate was only 12% in Arm B (q12w). Grade 3 HC (i.e. corrected Ca 1.5 - 1.74 mmol/l or hospitalisation indicated) was rare (0.3%), no grade 4 HC occurred. After 1 year of treatment, the rate of HC compared to the induction phase had decreased in Arm B but not in Arm A (A: 25%, B: 12%). Since HC improved in more patients in Arm B than in Arm A whereas it worsened in more patients in Arm A than in Arm B, a remarkable difference for HC resulted between the two arms. Rates of hypocalcemia and change of severity after week 16* Arm A (N = 177)Arm B (N = 174)Rates of hypocalcemian (%)n (%)Patients with hypocalcemia at any time49 (28%)46 (26%)Patients with hypocalcemia after week 16*44 (25%)21 (12%)   Change in hypocalcemia grade after week 16*for the 49 patients with hypocalcemiafor the 46 patients with hypocalcemiaWorsening25 (51%)8 (17%)Stable10 (20%)9 (20%)Improving14 (29%)29 (63%)   *week 16: i.e. the time where the schedules of DN begin to differ between Arm A and Arm BArm A: DN q4w for weeks 1 - 12 and likewise thereafter / Arm B: DN q4w for weeks 1 - 12 and q12w thereafter Conclusions In our trial up to 20% of all BC patients treated with DN experienced HC in the q4w induction phase despite mandatory supplementation of VitD and Ca. This rate is considerably higher than the numbers reported in the registration trials of DN (where it was 5.5% for BC). After the induction phase, HC is markedly reduced in the q12w arm compared to q4w. This suggests that DN given q12w has a more favorable long-term safety profile in terms of HC compared to DN q4w. Citation Format: Müller A, Templeton AJ, Hayoz S, Hawle H, Hasler-Strub U, Schwitter M, Pestalozzi BC, Pagani O, Bützberger P, Wehrhahn T, Rauch D, Inauen R, Betticher D, Zaman K, Bodmer A, Popescu RA, Rothschild S, Schardt J, Borner M, Fuhrer A, Schär C, Gillessen S, von Moos R, For the Swiss Group for Clinical Cancer Research (SAKK). Incidence of hypocalcemia in patients with metastatic breast cancer under treatment with denosumab: A non-inferiority phase III trial assessing prevention of symptomatic skeletal events (SSE) with denosumab administered every 4 weeks versus every 12 weeks: SAKK 96/12 (REDUSE) [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P1-18-01.