Safety of long-term denosumab therapy: results from the open label extension phase of two phase 3 studies in patients with metastatic breast and prostate cancer

Alison T Stopeck, Karim Fizazi, Jean-Jacques Body, Janet E Brown, Michael Carducci, Ingo Diel, Yasuhiro Fujiwara, Miguel Martín, Alexander Paterson, Katia Tonkin, Neal Shore, Paul Sieber, Frank Kueppers, Lawrence Karsh, Denise Yardley, Huei Wang, Tapan Maniar, Jorge Arellano, Ada Braun, Alison T Stopeck, Karim Fizazi, Jean-Jacques Body, Janet E Brown, Michael Carducci, Ingo Diel, Yasuhiro Fujiwara, Miguel Martín, Alexander Paterson, Katia Tonkin, Neal Shore, Paul Sieber, Frank Kueppers, Lawrence Karsh, Denise Yardley, Huei Wang, Tapan Maniar, Jorge Arellano, Ada Braun

Abstract

Purpose: Zoledronic acid (ZA) or denosumab treatment reduces skeletal-related events; however, the safety of prolonged therapy has not been adequately studied. Here, we describe safety results of extended denosumab therapy in patients with bone metastases from the open-label extension phase of two phase 3 trials.

Methods: Patients with metastatic breast or prostate cancer received subcutaneous denosumab 120 mg Q4W or intravenous ZA 4 mg Q4W in a double-blinded fashion. Denosumab demonstrated superior efficacy in the blinded treatment phase; thus, patients were offered open-label denosumab for up to an additional 2 years.

Results: Cumulative median (Q1, Q3) denosumab exposure was 19.1 (9.2, 32.2) months in the breast cancer trial (n = 1019) and 12.0 (5.6, 21.3) months in the prostate cancer trial (n = 942); 295 patients received denosumab for >3 years. No new safety signals were identified during the open-label phase, or among patients who switched from ZA to denosumab. During the blinded treatment phase, exposure-adjusted subject incidences of osteonecrosis of the jaw (ONJ) were 49 (1.9%) and 31 (1.2%) in the denosumab and ZA groups, respectively. In total, 32 (6.9%) and 25 (5.5 %) new cases of ONJ (not adjusted for exposure) were reported for patients continuing and switching to denosumab, respectively. The incidences of hypocalcemia were 4.3 and 3.1%, in patients continuing and switching to denosumab, respectively.

Conclusion: These results describe the safety profile of denosumab after long-term exposure, or after switching to denosumab from ZA. No new safety signals were identified. Hypocalcemia rates were similar in the blinded treatment and open-label phases. ONJ rates increased with increasing exposure to antiresorptives, consistent with previous reports.

Trial registration: ClinicalTrials.gov NCT00321464 NCT00321620.

Keywords: Bone metastases; Breast cancer; Denosumab; Osteonecrosis of the jaw; Prostate cancer; Zoledronic acid.

Figures

Fig. 1
Fig. 1
Study design and treatment schema, SC subcutaneous, IV intravenous, Q4W every 4 weeks
Fig. 2
Fig. 2
ONJ rates for the blinded treatment phases of the breast cancer and prostate cancer trials during the first year of treatment, subsequent years of treatment, and blinded treatment overall. Incidence rates are adjusted for patient-years of follow-up to reflect different lengths of time on study, and expressed per 100 patient-years of follow-up, calculated as a ratio of the total number of adjudicated positive ONJ events and the total subject-years of follow-up through either the end-of-study date or the blinded treatment phase cutoff date. ONJ osteonecrosis of the jaw *One additional patient in the zoledronic acid/denosumab group developed ONJ after the end-of-study date
Fig. 3
Fig. 3
Kaplan-Meier estimates of overall survival for the duration of the breast (a) and prostate (b) cancer studies. KM Kaplan-Meier, Q1, Q3

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