Bone metastases: can you teach an old drug new tricks?

Three of the four big cancers commonly metastasise to the bone
In 2008, an estimated 225,174 people in the seven major markets** will be diagnosed with bone metastases from cancers of the breast, lung, prostate, thyroid and the main form (85%) of kidney cancer, renal cell carcinoma.

The outlook for patients whose cancer has metastasised to the bone is grim: a third of advanced lung cancer patients will develop bone metastases and only five percent of these patients will live beyond five years after diagnosis. Almost 70% of advanced breast and prostate cancer patients develop bone metastases respectively, and only around a quarter of these patients are still alive after five years.

Patients with bone metastases are often affected with skeletal complications such as bone pain, skeletal fractures, hypercalcemia and spinal cord compression (where the tumour presses against the spinal cord), says Datamonitor cancer analyst Chandni Surti. “Although bisphosphonates reduce the risk of skeletal complications by up to 50%, they do not improve survival in the majority of advanced cancer patients.”

Prevention is better than cure

For over 18 years, bisphosphonates (pamidronate and clodronate) have been used to treat bone metastases. Bone metastases alter the normal bone remodelling process to cause excessive bone breakdown or bone formation. Bisphosphonates work by causing programmed cell death (apoptosis) of the cells actively involved in bone breakdown (osteoclasts). Roche/GlaxoSmithKline's Bondronat (ibandronate) and Novartis' Zometa (zoledronate) are newer and more potent bisphosphonates. These third-generation agents are now being investigated for their potential to prevent bone metastases in early stage cancer patients - a move that could completely transform the management of this adverse complication.

Unfortunately, physicians are currently unable to identify which cancer patients will develop bone metastases. Furthermore, it is difficult to predict which bone metastases patients are at a greater risk of developing skeletal complications, Surti says. “A highly unmet need would be addressed if bisphosphonate use can prevent bone metastases in early stage cancer patients. This would not only translate into a significant survival benefit, but also improve the quality of life of patients.”

In one small pilot study of 40 patients, Zometa prevented the development of bone metastases in 60% of patients compared to 10% of patients who received no bisphosphonate therapy at 12 months. Zometa and other bisphosphonates are currently undergoing further clinical investigation to fully determine their potential in preventing bone metastases.

Can newer agents break into the bone metastases market?

Two of the four bisphosphonates approved for use in bone metastases have already undergone patent expiry (pamidronate and clodronate), and patent expiries across the seven major markets** are also approaching for Bondronat in 2011 and Zometa in 2012 respectively.

It may be that the availability of cheaper generic bisphosphonates poses a threat to newer, more costly agents in development for bone metastases, Ms Surti says. “On the other hand, new agents could see rapid uptake if they demonstrate higher efficacy and/or safety profiles compared to bisphosphonates.

“It is likely that the approaching patent expiries will present an opportunity for emerging agents to enter the bone metastases market and possibly spur some further interest amongst drug developers,” she says.

Amgen/Daiichi Sankyo's denosumab shows promise

At first look, the bone metastases drug development pipeline may seem under-sized for a deadly metastases with a relatively large patient population that spans a variety of major cancer types. However, the presence of effective agents from big pharma companies such as Novartis and Roche/GlaxoSmithKline has likely reduced market interest for new drug developers. However, while bisphosphonates dominate bone metastases treatment, there is still much scope left to improve treatment outcomes.

One promising agent, denosumab is currently in Phase III development for bone metastases. Denosumab is a new targeted therapy being developed by Amgen in the EU and US and Daiichi Sankyo in Japan. It is a fully human monoclonal antibody that selectively targets a major mediator of bone breakdown, RANKL (receptor activator of nuclear êB ligand). In addition to its more targeted mechanism of action, some physicians state that denosumab's subcutaneous route of administration will prove advantageous over intravenous bisphosphonates, making it more convenient for patients as well as medical staff, Ms Surti says.

“The ongoing Phase III trials are investigating denosumab's ability to reduce skeletal related events when compared to the intravenous bisphosphonate Zometa. Denosumab has already shown promise in Phase II bone metastases trials in breast, prostate, multiple myeloma and other advanced cancer patients.”

* Stakeholder Opinions: Bone Metastases - Impending patent expiries may help make or break newer agents

Datamonitor's report Stakeholder Opinions: Bone Metastases - Impending patent expiries may help make or break newer agents examines key issues in bone metastases, including mechanisms of normal and altered bone metabolism, epidemiology data, current treatment options, unmet needs, analysis of pipeline drugs in direct development for bone metastases and key stakeholder opinions.