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

Abstract

PurposeZoledronic 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.MethodsPatients 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.ResultsCumulative 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.ConclusionThese 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.

Definition and estimation of osteonecrosis of jaw (ONJ), and optimal duration of antiresorptive treatment in bone metastatic cancer patients: supplementary data from the denosumab extension study?

“…In their recent article, Stopeck et al [1] concluded that denosumab confirms its known safety profile even after longterm exposure, or after switching to it from zoledronic acid, and that osteonecrosis of jaws (ONJ) rates increased with increasing exposure to antiresorptives, consistent with previous reports. This is based on the open label extension phase of two phase 3 studies in patients with breast and prostate cancer with bone metastases who were randomized to receive denosumab or zoledronic acid (ZA) [2,3].…”

“…We collected data from the text and the tables of the paper published by Stopeck et al [1] and summarized them in a new table (Table 1).…”

“…Of importance, such data were recorded after a relatively short observation time, being the median (Q1, Q3) time on study 12.1 (5.4, 19.4) months for patients in the ZA group and 12.6 (5.6, 19.4) months for patients in the denosumab group [10]. We believe that it would be of great value if the authors of the extension study [1] could report the number of Bpotential ONJ^cases (defined as above) observed in the breast and prostate cancer population of the extension study, and compare them with those of the blinded study, and those among patients who declined shift to denosumab, if available.…”

“…Patients initially randomized to denosumab (denosumab/ denosumab group) continued to receive denosumab at 120 mg Q4W whereas patients on ZA were switched to denosumab in the open-label phase (ZA/denosumab group) at 120 mg Q4W starting 4 weeks from their last ZA dose. Patients who declined further therapy in the open-label extension phase, or who did not complete the blinded treatment phase, continued follow-up for survival every 12 weeks (Q12W) for up to 2 years after their last dose.We collected data from the text and the tables of the paper published by Stopeck et al [1] and summarized them in a new table (Table 1).Although authors' conclusions are quite reassuring both in terms of denosumab safety and efficacy, it is noteworthy that the median exposure of patients to denosumab in the extension phase study is lower than expected, even in the presence of a longer range. The final median exposure of the 318 denosumab/denosumab breast cancer patients is 19.1 months (range 0.1-59.8), not much longer than that registered for the whole cohort of the 1019 breast cancer patient population enrolled in the blinded phase, that was 17.6 months (range 0-23.7).…”

Multifocal brown tumor of the maxilla and mandible in primary hyperparathyroidism – diagnostic challenges and literature review

“…In any case, the safety profile of DMab after long-term exposure is 19.1 months in breast cancer and 12 months in prostate cancer. 13 Finally, metastatic kidney cancer is a special case. This patient setting is particularly susceptible to ONJ due to the concomitant use of antiangiogenic drugs that block vascular endothelial growth factor (VEGF).…”