Cabozantinib (cabo), has many of us prostate cancer survivor, educators and researchers simply scratching their heads. In trials, Cabozantinib demonstrated what some people have characterized as mind boggling activity against bone metastases. In trials the drug led to partial or complete resolution of bone scans in a substantial portion of patients with cancer, including prostate, breast and lung cancer.
Despite the intriguing nature of the data there is still an ongoing debate as to what those bone scan findings actually mean. Bone scans do not visualize actual bone mets but the metabolic activity they induce. This is in contrast to CT scans that detect tumors in organs other than the bone, by giving a direct measurement of tumors’ size and shape. Bone scans are an indirect measure of bone mets and could potentially misrepresent what is actually taking place.
The question becomes, is cabozantinib effecting the metastases or is it doing something to the bone environment without actually effecting the metastases? Some critics have claimed that the resolution of bone mets is a mere artifact that has to do with the imaging technique being used. This claim is enhanced because of the short time it takes to see an effect with cabozantinib (sometimes a matter of several weeks), which appears too good to be true given current understanding of bone metabolism. And of course Cabozantinib has no effect on PSA levels which is the established blood marker in prostate cancer (however, we cannot forget the Provenge has been shown to extend survival without effecting PSA measures).
We will need to wait for a definitive answer by having a large randomized trial with overall survival as a primary endpoint. However, cabozantinib does appear to be active by effecting pain.
At the recent ASCO 2011 meeting there was evidence presented that cabo showed a correlation between lack of overall disease progression and bone scan resolution as well as anecdotal evidence of bone met shrinkage using MRI, which directly measures the lesions.
Also at ASCO there was safety concerns raised as there have been reported issues with cabozantinib. The drug led to death in 6 (1.2%) out of 490 patients included in the data pool. Although initially alarming, this rate of mortality (assuming all cases are related to the drug) is in line with other approved regimens in comparable patient populations.
A ~1% mortality rate is acceptable in late stage disease but in earlier treatment lines safety requirements are stricter and treatment duration could be longer. In addition, such a safety profile might prevent combining cabo with other treatments, which seems desirable given the potential synergies with other drugs.
In order to tackle this issue, a trial has been initiated by Dr. Matthew Smith from Mass. General Hospital is evaluating lower doses of cabozantinib in prostate cancer patients. The idea is decreasing the dose to a level where the bone scan resolution is no longer observed and use the minimal dose with activity. Although no formal data was published, Exelixis, the company developing cabozantinib stated that after evaluating a regimen utilizing 40% of the original dose, investigators are moving to an even lower dose (20% of the original dose). This implies cabo is still active even when given at less than half of the original dose. It is too early to tell whether using lower doses will diminish the drug’s activity or whether the safety profile will improve. Nevertheless, these preliminary signs bode well for the future development of cabo across multiple treatment lines, from bone met prevention to full blown metastatic disease.
Bone metastases occur in multiple cancer types (including advanced prostate cancer) and are believed to be a major cause of mortality (directly or indirectly), but targeting bone mets has not been proven as clinically meaningful. However, just over 2 months ago, Norway-based Algeta announced positive top-line results from a phase III trial evaluating its bone met targeting drug, Alpharadin. Alpharadin increased survival of prostate cancer patients with bone mets from 11.2 to 14 months. The drug is a radioisotope that preferentially accumulates in bone metastases making it the first ever drug to prolong survival in cancer by exclusively targeting bone lesions.
Algeta’s success serves as a clear validation for targeting bone mets, proving it can prolong survival. However, Alpharadin has no visible effect on bone scans but has an effect on pain and bone markers.
So, are the positive effects of Cabo on bone scans merely an artifact, meaning that cabo is irrelevant in the context of bone met targeting and for the treatment of men with advanced prostate cancer? If cabo’s bone effect is real, there is a good possibility for it to have a survival effect based on Alpharadin’s proof of concept.
Only time and research will provide these answers.
Joel T Nowak, M.A., M.S.W.