Precision Medicine on the Horizon for Prostate Cancer

Tomasz M. Beer, MD, FACP

While still in its early stages, integrative genomic testing could be the future for personalizing therapy for patients with castration-resistant prostate cancer (CRPC), according to Tomasz M. Beer, MD, FACP.

In an interview withTargeted Oncology, Beer, deputy director, Knight Cancer Institute, Oregon Health and Science University, explained that understanding the genetic makeup of CRPC could lead to new treatments, both single-agents and combinations. One of the most recent examples was the discovery ofBRCAgenetic mutations within CRPC, he said. WhileBRCAmutations are mostly associated with breast and ovarian cancers, this discovery could provide a new avenue for treating men with CRPC.

In the interview, Beer discussed the current state of genetic testing for prostate cancer and changes on the horizon that are currently being explored in clinical trials.

TARGETED ONCOLOGY:What is currently known about the genetics of prostate cancer?

BEER:What we are beginning to see in the field is the delivery on the promise of personalized therapy selection in patients with advanced castration-resistant metastatic prostate cancer. What's happening is that several groups are analyzing individual patient's tumors, typically from a metastatic site biopsy, and deeply sequencing the genetic material from those cancers. This is enabling us to really understand what the defects and abnormalities are that are responsible for cancer growth and progression.

There is a lot of work left to be done. We haven't solved the whole puzzle, but there have been some exciting discoveries about abnormalities that were unexpected. If these findings are confirmed, these could have real implications for specific treatments for those patients.

TARGETED ONCOLOGY:What were some of the abnormalities that were discovered that would be able to advance the treatment paradigm?

BEER:The most interesting and compelling discovery was the presence of DNA repair defects. Most commonly and best known in the DNA repair defect world are theBRCAgenes, or the genes that are the breast cancer susceptibility genes. Many people have heard of these genes as the ones that, when inherited, put a woman at a high risk for developing breast cancer. It turns out that these genes can also play a role in prostate cancer. They are present in 20% of advanced prostate cancers.

About half of those 20% of patients inherit theBRCAgenes, which was a surprise. The other half were acquired, which means that the tumor ends up having a mutation in that gene even though the patient has normal genetic makeup, which was also a surprise. The important part about that is there are drugs that are potentially quite effective in treating cancers that have these defects. A companion study from the United Kingdom reported a very high response rate to agents called PARP inhibitors in patients who harbor these mutations.

A discovery has been made that was unexpected, which is that essentially breast cancer mutations play a role in a significant minority of prostate cancers. Studies are beginning to show that there might be effective therapies for those patients, which are therapies that we would never ordinarily prescribe in prostate cancer.

TARGETED ONCOLOGY:How will a better understanding of the genetics help expand the current treatment armamentarium for prostate cancer?

BEER:We're not quite "there" yet. Anytime we have exciting genomic news, patients will come in and ask, "Can I have this test? Can I have this therapy?" It's not quite ready yet. A lot of these tests in prostate cancer are still investigational. There is not a clinical-grade whole genome that is easy to obtain and affordable. A little more time and work needs to be done before these tests are readily available.

I think the time is coming in the relatively near future where understanding the genetic makeup of each person's cancer and being able to select therapies based on those findings. Even today, we're taking that approach to recruit patients to clinical trials. Any number of clinical trials now that are dealing with targeted therapies for patients that harbor specific targets, we begin with a tumor analysis and allocate therapies based on what we find. I'm seeing a relatively near future for this, probably within the next two or three years, where this kind of approach begins to be a real component to how we take care of patients with prostate cancer.

TARGETED ONCOLOGY:What are the next steps for making these genomic tests a little more mainstream?

BEER:First of all, studies are ongoing to understand and expand the initial findings. The findings on the genetic abnormalities came from an analysis of about 150 patients, which is not a small number, but with certain global "dream teams" coming together, we expect to see analyses of between 600 and 800 patients. So we can gather a lot more data and see what comes up.

Second, studies that document that these prostate cancers can respond to specific agents are underway as well. We are going to see if we can confirm the findings fro the trial in United Kingdom and develop strategies on that as well. All that work needs to be done, and then of course we need these research tests to be converted to clinical-grade tests that are readily available. There are a number of laboratories, academic and corporate, that are providing these kinds of tests, but the field is evolving very quickly.

Not all these tests are testing for all the defects that we're interested in because literally within the last few months, additional defects have been identified. I think we will see a refinement and standardization of the assays before they can become a part of routine care.

TARGETED ONCOLOGY:Do you think these tests could result in new combinations or treatments?

BEER:There is a lot of potential for genomic tests to result in new treatments where a target like a DNA repair mutation is identified, and an agent such as carboplatin or PARP inhibitor, could be prescribed based on that defect. That's a new treatment.

Combinations we're not quite there yet. Hypothetically, if we find cancers that have two targetable defects at the same time, it would certainly make sense to explore targeting both with a combination. In clinical trials, that's coming fairly soon. Getting this into routine practice is going to take some work. There need to be some FDA approvals and there need to be some reimbursement issues sorted out. What we can do in studies is not always practically possible in routine care until we're a little further down the road when the results have been published and accepted.

So there needs to be a little more work on that front, but I do think it's coming.