THE "NEW" PROSTATE CANCER INFOLINK

A media release issued yesterday by Amgen claims that denosumab “demonstrated superiority” over zoledronate (Zometa) in a randomized, multi-center, Phase III clinical trial in prostate cancer patients with bone metastases.

Denosumab is an investigational product in development of the prevention of bone loss and destruction associated with hormone therapy-induced bone loss in breast and prostate cancers, for the prevention of skeletal related events (SREs) resulting from the spread of cancer to the bone, and for its potential to delay bone metastases in prostate cancer. Zoledronate is a Novartis product that is the current “standard of care” for similar clinical indications.

Amgen has made great efforts to demonstrate the potential clinical value of denosumab, including trials involving over 19,000 patients to date. Denosumab is a fully humanized monoclonal antibody or MAb that targets the so-called RANK ligand or RANK-L. RANK-L is an important regulator of the development and growth of cells called osteoclasts, which are responsible for the normal breakdown of bone over time, but which can become over-active in some cancer patients, resulting in an acceleration in the rate of bone destruction.

Here is a summary of the key points of this trial, including Amgen’s statement of the results:

• The trial enrolled 1,901 patients from several countries, including the USA, all of whom had hormone-refractory, metastatic prostate cancer, with metastases evident on bone scans.
• The average (mean) age of the patients was 71 years.
• The patients were randomized to receive treatment with either denosumab (120 mg injected subcutaneously every 4 weeks) or zoledronate (4 mg administered intravenously every 4 weeks).
• Denosumab significantly delayed the time to the first on-study SRE (a fracture, the need for radiation to bone, the need for surgery to bone, or spinal cord compression) for longer than zoledronate (hazard ratio = 0.82).
• Denosumab also significantly reduced the rate of multiple SREs compared to zoledronate (hazard ratio = 0.82).
• Overall rates of adverse events and serious adverse events, including infections, were “generally similar” between the patients in the two arms of the trial
• Osteonecrosis of the jaw (ONJ) was observed in 22 patients treated with denosumab and in 12 patients receiving zoledronate, but apparently this difference was not statistically significant.
• Hypocalcemia was “more frequent” in the denosumab arm (as has been observed in other trials already reported).
• Overall patient survival and time to cancer progression were “balanced” between the two treatment arms.

Clearly there are a lot of details about this trial that are still to come, and this media release is primarily provided as base information for Amgen’s investors. However, there are some data here that are highly relevant for patients who may need to be treated with one or other of these drugs once denosumab is approved by the FDA and other regulatory bodies. (Such approval is projected for later this year.)

On the “upside,” a statistically significant hazard ratio of 0.82 means that denosumab reduces the risk for SREs and the rate of multiple SREs by about 20 percent compared to zoledronate. Since zoledronate is considered to be very good at reducing the risk and rate of SREs, it has to be said that a further reduction of this risk by 20 percent is a very good result (for Amgen and potentially for patients). On the “downside,” however, denosumab is apparently associated with at least the same risk as zoledronate for ONJ (a significant and potential serious side effect) and it is already known to be associated with a higher level of risk for hypocalcemia (lowered blood levels of calcium).

Will denosumab really be a “better” option for patients than zoledronate when it comes to the crunch? Frankly, based on the information currently available, it is very hard to tell. The potential problem with all monoclonal antibody therapies is that they may also be associated with very small risks for very serious complications that can lead to a patient’s death. Even though Amgen has treated a lot of patients in clinical trials, we may only know what the “real” risk for such very serious side effects is when the product gets to market.

Filed under: Management, Drugs in development Tagged: | bone loss, SREs, denosumab, zoledronate, Zometa