We have become very fortunate over the last 6 years because our arsenal of potential drugs to treat advanced, metastatic prostate cancer has grown. All of our new drugs extend life and most offer palliation of pain. As I have discussed in prior posts we are still in a quandary about how best to sequence these new drugs. In addition, not all of us are going to be sensitive to all the drugs.
The costs for these new drugs range from $4,500 per month to $145,000 for a complete treatment protocol. They are not cheap; they will involve a significant investment from us personally in the cost of our co-pays and deductibles; they will involve large costs to our insurance company and to our society.
Spending these huge sums of money when a treatment works is very different from spending this money for treatments that don’t provide any benefit. Given that not all the drugs will provide a benefit to a specific individual, we need to find intelligent decision aides that will allow us to know in advanced which drugs we should give to a specific man and which drugs we should simply cross off the list.
To date, the best decision aides of this type are call biomarkers. In 1998, the National Institutes of Health Biomarkers Definitions Working Group defined a biomarker as “a characteristic that is objectively measured and evaluated as an indicator of normal biological processes, pathogenic processes, or pharmacologic responses to a therapeutic intervention.” Identifying biomarkers that would let us know if a specific treatment would provide any benefit would allow for better clinical decisions and significant financial savings.
Identifying biomarkers would allow us to know in advance what drugs we should use in which men. This includes prostate cancer as well as any other disease or ailment we wish to treat.
We do know that androgen receptor targeting is the cornerstone of prostate cancer treatment. The frustrating fact is that our tumors will eventually become “castration-resistant” or no longer sensitive to androgen deprivation therapy (ADT). Even in men who are castrate resistant, androgen signaling can still be effectively targeted. Drugs such as abiraterone (Zytiga) and enzalutamide (Xtandi) inhibit the androgen signaling axis.
Romanel et al. analyzed tumor DNA taken from blood samples from 97 men with castration-resistant prostate cancer at different times during the course of treatment with Zytiga. They found that although some new mutations emerged in these men during the therapy they also found that androgen receptor amplifications were present from the beginning of treatment and correlated with Zytiga resistance. This finding clearly suggests that detection of these amplifications in the DNA is an excellent biomarker candidate that should be explored and possibly be useful for identifying Zytiga resistant prostate cancers before starting a man on this treatment.
Other related work in the development of biomarkers in men with metastatic prostate cancer has been the work of Dr Antonarakis’ group from The Johns Hopkins Medical Center. Dr. Antonarakis’s work has shown that an alternative splicing form of AR mRNA (AR-V7) taken from circulating tumor cells (CTCs) also correlated with response to taxanes (chemotherapy for prostate cancer) and resistance to Zytiga and Xtandi.
We have the ability to both identify alterations in circulating cell-free DNA from the blood and apply them to clinical interventions. This relatively noninvasive method (a blood draw) will allow us to make better clinical decisions and save financial resources.
We need to continue funding the biomarker discovery efforts being made. It has proven to be highly encouraging with data that if validated, can quickly become a regular part of our treatment processes.
Sci Transl Med. Published online November 4, 2015.