Evenity (Romosozumab) Cancer Risk Signal Review

Does Evenity raise cancer risk?

The Evenity (romosozumab-aqqg) label does not present cancer as a risk of treatment. Its boxed warning is titled "POTENTIAL RISK OF MYOCARDIAL INFARCTION, STROKE AND CARDIOVASCULAR DEATH" and does not mention malignancy [1]. The Warnings and Precautions section covers major adverse cardiac events, hypersensitivity, hypocalcemia, osteonecrosis of the jaw and atypical femoral fracture; cancer is not one of them [1]. The contraindications are pre-existing hypocalcemia and a history of systemic hypersensitivity to romosozumab or its components [1].

The one place cancer appears in the label warnings

The label lists cancer, radiotherapy, poor oral hygiene and pre-existing dental disease or infection among risk factors for osteonecrosis of the jaw (ONJ). It also says that drugs associated with ONJ (chemotherapy, bisphosphonates, denosumab, angiogenesis inhibitors and corticosteroids) taken at the same time may increase the risk [1]. The label says a routine oral examination should be performed by the prescriber before treatment starts [1]. For someone with a cancer history, the label identifies cancer as one factor that may increase the risk of ONJ during Evenity treatment [1].

What FRAME and ARCH measured

FRAME enrolled 7,180 postmenopausal women and randomly assigned them to monthly romosozumab 210 mg or placebo for 12 months, followed by denosumab for 12 months [2]. New vertebral fractures were 0.5% versus 1.8% at 12 months (73% lower) and 0.6% versus 2.5% at 24 months; clinical fractures at 12 months were 1.6% versus 2.5% (36% lower, P=0.008) [2].

ARCH randomized 4,093 postmenopausal women with osteoporosis and a fragility fracture to monthly romosozumab or weekly alendronate 70 mg for 12 months, then alendronate in both groups [3]. At 24 months, new vertebral fractures were 6.2% versus 11.9% (48% lower, P<0.001) and clinical fractures 9.7% versus 13.0% (27% lower) [3].

The cardiovascular signal behind the boxed warning came from the 12-month alendronate-controlled trial: adjudicated major adverse cardiac events were 2.0% on Evenity versus 1.1% on alendronate, hazard ratio 1.87. In the placebo-controlled FRAME trial they were 0.8% in both groups, hazard ratio 1.03 [1].

Can adverse event reports answer it?

The FDA states that an adverse event report does not establish that the drug caused the event, that reporting data cannot be used to estimate how often an event occurs, and that reports may be duplicated or incomplete [4]. Reports alone therefore cannot show that Evenity caused cancer or establish how often it occurs [4].

What the label does warn about

The boxed warning says Evenity may increase the risk of myocardial infarction, stroke and cardiovascular death. The label says it should not be initiated in patients who have had a myocardial infarction or stroke within the preceding year, that benefits and risks should be weighed in patients with other cardiovascular risk factors, and that Evenity should be discontinued if a myocardial infarction or stroke occurs during therapy [1]. The label gives the dose as 210 mg subcutaneously once a month for 12 monthly doses, administered by a healthcare provider, with calcium and vitamin D supplementation during treatment [1].