Many of the posts that I have written discussed the need for evaluating our current advanced prostate cancer drugs in both combinations and their sequencing. We have a number of new drugs, but we don’t understand how best to sequence them, or whether or not some drugs would do better and extend life by taking them in combination. Actually, my last post mentioned that perhaps the next big breakthrough will not be a new drug approval, but be a better understanding how to better sequence and combine the currently approved drugs.
Understanding how we get to effective clinical trials, which look at these issues, is important. For example, we know that Abiraterone (Zytiga) improves the overall survival of men with metastatic castration resistant prostate cancer. We also know that cross or adaptive resistance to abiraterone develops, limiting its activity and ultimately its efficacy.
On the assumption that rational combinations of drugs that have different mechanisms of action could overcome these limiting resistance mechanisms, researchers have studied the molecular and phenotypic effects of the combination of a drug called cabozantinib used in combination with Zytiga.
The researchers used three prostate cancer cell lines in vitro to evaluate the molecular and anti-proliferative effects of the single agents and the combination of cabozantinib and abiraterone.
Their in vitro proliferation studies demonstrated single agent doses of abiraterone and cabozantinib inhibit prostate cancer cell proliferation in a dose-dependent manner and the anti-cancer activity of abiraterone is enhanced when it is combined with cabozantinib.
They also found in their mouse model experiments that cabozantinib in combination with Zytiga could improve the anti-tumor activity of Zytiga by enhancing the ability of Zytiga to inhibit the AR activity and also by stimulating IGF-1R phosphorylation with downstream activation of MEK1/2 and ERK1/2 which is a potential adaptive resistance mechanism.
Given these mouse studies it is now appropriate for us to see both follow up studies, as well as possible phase I clinical trial combining cabozantinib with Zytiga. Understanding the role of combination therapies as well as how we decide which drugs should be combined is important. This is just one example of good basic science moving us a step closer to better clinical solutions to treating advanced prostate cancer.
Clinical cancer research; American Association for Cancer Research 2015 Aug 19 [Epub ahead of print]; Xiaodong Wang, Ying Huang, Amanda L Christie, Michaela Bowden, Gwo-Shu M Lee, Philip W Kantoff, Christopher J Sweeney.