Finally, I want to chat a little bit about PARP inhibitors which I think represent one
of the beginnings of one of personalized therapy for prostate cancer and are linked to genetic
testing, particularly for tumors. And when we think about the genetic analysis of tumors
I think about this landmark paper which is now four years old where about 150 biopsies
were obtained from men with advanced metastatic castration-resistant prostate cancer. This
was really revolutionary work. In leukemia, this is old hat. You can draw blood for leukemia
and analyze these cells routinely and our leukemia colleagues have been doing it for
decades, but in prostate cancer, this was really new because analyzing particularly
bone metastases has been technically quite difficult and biopsies have not been routinely
obtained. This is a very detailed map of what was seen, and I'm not going to go through
it in detail, but what you can see in the columns is individual patients. So this is
actually data from individual human beings; it's not some sort of summary data. And across,
you see alterations in various genes. So the top you see a lot of color and those are really
commonly altered genes. The top of the line is the androgen receptor, this is a testosterone-driven
disease, so it's really common to have extra copies of the androgen receptor or mutations
in the androgen receptor, etc. P53, P10, and the so-called ETS genes are really commonly
altered. But down below, you see a lot of rare mutations that don't occur in many patients,
but when they do occur they may open the door for individualized therapy. That result led
us to think about the possibility that inherited genetic defects are more common than previously
suspected and Colin Pritchard reported this paper the next year in 2016 showing that about
12% of men with metastatic prostate cancer harbor a cancer predisposition mutation that
may be relevant both for their therapy and choices of treatment, but also for their family
and so we've begun to offer routine testing for inherited genetic mutations for men with
advanced prostate cancer as a result of this report.
How are we using this biomarker data to treat patients today? Well, we have pembrolizumab,
a PD1 inhibitor immune therapy approved for patients who harbor a particular DNA repair
deficiency also known as microsatellite instability. This is rare in prostate cancer. We see it
in a couple percent of patients, but when we do see it, we expect to have a good chance
of a significant response to this form of immune therapy. PARP inhibitors are drugs
that can be effective for patients with mutations in another class of DNA repair genes, particularly
BRCA2 and BRCA1. Those of you who've paid attention to breast cancer have heard of these
breast cancer predisposition genes. There are not known to be very important in prostate
cancer as well. I've already mentioned gallium PSMA imaging as potentially useful in selecting
PSMA directed therapy. There are lots of other molecularly targeted therapy trials. This
is just an example of the NCI MATCH trial which is offering specific molecular agents
for a variety of defects. So when we sequence a patient's tumor deeply and find these rare
mutations, one of the things we look to is this trial to see if there is a novel agent
available for that particular patient based on the genetic sequence. But I think using
single drugs for single mutations is unlikely to be the definitive solution to prostate
cancer. I think we're going to need multi-agent targeted therapies just like we do in infectious
disease, and to that end at OHSU we've launched a trial called SMART which stands for Serial
Management of Molecular and our Contextual Responses to Therapy. This started in breast
cancer, but in the near future we're going to open a prostate cancer arm and this trial
differs from other approaches in that we analyze not just the DNA and RNA in the tumors, but
we look at protein levels, we look at cell structure with electron microscopy and we
aim to use more than one targeted drug simultaneously and rebiopsy a tumor fairly early into therapy—maybe
4-6 weeks—to see what's going on biologically and try to adjust our therapy if we begin
to detect the early development of cancer adaptation to our treatment before there is
overt cancer progression.