Incidence of hypocalcemia in a non-inferiority phase III trial assessing prevention of symptomatic skeletal events (SSE) with denosumab (DN) administered every 4 weeks (q4w) versus every 12 weeks (q12w): SAKK 96/12 (REDUSE)

Moos, Roger von; Hawle, Hanne; Hayoz, S.; Cathomas, Richard; Müller, Andreas; Schmid, Sabine; Pagani, Olivia; Wehrhahn, T; Rauch, Daniel; Anchisi, Sandro; Hermanns, Thomas; Fehr, Mathias K.; Stoll, Susanna; Bützberger, P; Zweifel, Martin; Huber, Urs; Fuhrer, AC; Schär, Corinne; Gillessen, Silke; Templeton, AJ

doi:10.1093/annonc/mdy300.020

Cited by 3 publications

(4 citation statements)

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“…Interestingly, rate of hypocalcemia in this trial was much higher than observed in registration trials despite mandatory vitamin D and calcium supplementation (31.6% vs <15%). [36][37][38]…”

Section: Recent and Ongoing Randomized Trialsmentioning

confidence: 99%

Prevention of Skeletal-Related Events With Extended-Interval Denosumab: A Review of the Literature

Keisner

2023

Ann Pharmacother

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Objective: To review published clinical trial data related to efficacy and safety of administering denosumab at extended dosing intervals for prevention of skeletal-related events (SREs) in cancer patients. Data Sources: A literature search of PubMed was performed (January 2006 to February 2023) using the following search terms: denosumab, bone metastasis, bone lesions, and lytic lesions. Abstracts from conferences, article bibliographies, and product monographs were also reviewed. Study Selection and Data Extraction: Relevant English-language studies were considered. Data Synthesis: Early phase II denosumab trials included treatment arms that utilized extended-interval denosumab, and various retrospective reviews, meta-analyses, and prospective trials have included extended-interval regimens. Most recently, the ongoing randomized REDUSE trial is comparing the efficacy and safety of extended-interval denosumab to standard dosing. At this time, the best available data are restricted to small, randomized trials not designed to compare efficacy and safety of extended-interval denosumab to conventional dosing and did not use consistent endpoints. Furthermore, primary endpoints of available trials largely consisted of surrogate markers of efficacy that may not be reflective of clinical outcomes. Relevance to Patient Care and Clinical Practice: Historically, denosumab has been dosed at 4-week intervals for prevention of SREs. If efficacy is maintained, extending the dosing interval could potentially reduce toxicity, drug cost, and clinic visits compared to every 4-week dosing. Conclusions: At this time, data demonstrating efficacy and safety of extended-interval denosumab remain limited, and the results of the REDUSE trial are eagerly anticipated to help answer remaining questions.

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Section: Recent and Ongoing Randomized Trialsmentioning

confidence: 99%

Prevention of Skeletal-Related Events With Extended-Interval Denosumab: A Review of the Literature

Keisner

2023

Ann Pharmacother

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“…However, the incidences of hypocalcaemia and serious hypocalcaemia are higher with denosumab [102], as potent inhibition of osteoclast function reduces the amount of skeletal calcium released into the circulation, while the incidence of renal toxicity is higher with ZA [53]. Recent data show that the incidence of hypocalcaemia in patients receiving denosumab can be as high as 30% despite mandatory Vitamin D and calcium substitution, although Grade 3 + hypocalcaemia was rare (1.3%) [103]. Unlike ZA, however, denosumab is not cleared by the kidneys [104].…”

Section: Rankl-targeted Monoclonal Antibodies: Denosumabmentioning

confidence: 99%

“…Other risk factors for hypocalcaemia include prostate cancer or small-cell lung cancer, reduced creatinine clearance, and higher baseline levels of the bone turnover markers urinary N-telopeptide of type I collagen and bone-specific alkaline phosphatase [105]. Recent data have shown, however, that the appearance of hypocalcaemia is very rare after 12 months of treatment [103].…”

Section: Rankl-targeted Monoclonal Antibodies: Denosumabmentioning

confidence: 99%

“…Extended dosing intervals or intermittent therapy may be used in practice, and the published data comparing different ZA dosing schedules are described above [74][75][76]. Studies investigating 4-weekly vs 12-weekly administration of denosumab are also underway (ClinicalTrials.gov: NCT02721433; NCT02051218 [103]). Additional areas in which research is needed include strategies to optimise the risk-benefit ratio of treatment with bisphosphonates and denosumab, and their use in patients with very severe disease.…”

Section: The Futurementioning

confidence: 99%

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Management of bone health in solid tumours: From bisphosphonates to a monoclonal antibody

Moos

Costa

Gonzalez-Suarez

et al. 2019

Cancer Treatment Reviews

105

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Patients with solid tumours are at risk of impaired bone health from metastases and cancer therapy-induced bone loss (CTIBL). We review medical management of bone health in patients with solid tumours over the past 30 years, from first-generation bisphosphonates to the receptor activator of nuclear factor κB ligand (RANKL)targeted monoclonal antibody, denosumab. In the 1980s, first-generation bisphosphonates were shown to reduce the incidence of skeletal-related events (SREs) in patients with breast cancer. Subsequently, more potent secondand third-generation bisphosphonates were developed, particularly zoledronic acid (ZA). Head-to-head studies showed that ZA was significantly more effective than pamidronate for reducing SREs in patients with breast and castrate-resistant prostate cancer (CRPC), becoming the standard of care for more than a decade. The RANKL inhibitor denosumab was licensed in 2010, and head-to-head studies and integrated analyses confirmed its superiority to ZA for preventing SREs, particularly in breast cancer and CRPC. Bisphosphonates and denosumab have also been investigated for prevention of CTIBL in patients receiving hormonal therapy for breast and prostate cancer, and denosumab is licensed in this indication. Despite advances in management of bone health, several issues remain, notably the optimal time to initiate therapy, duration of therapy, and dosing frequency, and how to avoid toxicity, particularly with long-term treatment. In summary, introduction of ZA and denosumab has protected patients with bone metastasis from serious bone complications and improved their quality of life. Ongoing research will hopefully guide the optimal use of these agents to help maintain bone health in patients with solid tumours.

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Are bone targeted agents still useful in times of immunotherapy? The SAKK 80/19 BTA pilot study

Mark,

Mora,

Winder

et al. 2024

Bone Reports

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Incidence of hypocalcemia in a non-inferiority phase III trial assessing prevention of symptomatic skeletal events (SSE) with denosumab (DN) administered every 4 weeks (q4w) versus every 12 weeks (q12w): SAKK 96/12 (REDUSE)

Cited by 3 publications

References 0 publications

Prevention of Skeletal-Related Events With Extended-Interval Denosumab: A Review of the Literature

Prevention of Skeletal-Related Events With Extended-Interval Denosumab: A Review of the Literature

Management of bone health in solid tumours: From bisphosphonates to a monoclonal antibody

Are bone targeted agents still useful in times of immunotherapy? The SAKK 80/19 BTA pilot study

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