So, Dr. Scholz, today we're talking about men who've failed first-generation hormone
therapy like Lupron and things of that nature. Now, men have been on Lupron in this situation,
usually for quite some time, and they kind of have this feeling like, okay we're checking
the PSA-level and maybe they're seeing a slow rise. Now, I know in PCRI, thanks to your
training, we've always talked about the difference of how a man has to think when he's on Lupron
versus when his PSA is rising and it's a different game. So, really, my question is, Does a man
go all in and treat this very aggressively? Are there certain steps and sequences that
he should take? What are your thoughts?
So, we're talking about androgen independence; we're talking about—I hate the word—castrate-resistant.
In our stages of blue system, we talk about it as Low-Royal and it's a major watershed
event because Lupron, as you pointed out, has been working for many years and if our
effective treatment stops working, then the situation is defined by finding a solution.
But there's a lot of solutions now and it's hard to know which one is best. The rate of
PSA rise gives you a clue as to how serious it is. In the studies that were done for the
approval of Zytiga and Xtandi and these medicines, they looked at the PSA doubling time and if
it was going up really quickly, i.e. doubling in less than 10 months, then that was justification
for going on these medicines. One of the things I find intriguing about what we should be
doing at this point because we know we're entering into a time of more serious prostate
cancer—castrate-resistant prostate cancer—should we be using our medicines one at a time—use
them up one at a time—and stretch out the time that we can use them, or is it better
for patients to go on two or three medicines right from the get-go to try and really mop
up the cancer and buy a long remission. If you look at those two different approaches,
usually the latter approach—combination approach—has translated into better long-term
outcomes, but it's a little more confusing in prostate cancer because long-term outcomes
in prostate cancer could mean 10-20 years, so you could argue that sometimes giving combinations
is an overkill. So, the doubling time probably guides that decision about whether to go with
a combination or just to give one medicine and, of course, the age of the patient. If
we can keep someone alive for 5-10 years and they're already 85 years old, then a simpler
approach is very reasonable. Perhaps just something like Xtandi or Zytiga as a single
agent. But if someone is younger and the PSA is going up quickly, I think that a combination
approach is a much more attractive way to go and that, for me, would mean some sort
of immune therapy and also in combination with a second-generation hormone medicine
like Xtandi or Zytiga. And, the problem is that if men's PSAs are very low, immune therapy
with, say, Provenge is not necessarily covered by insurance unless they can find a metastatic
site and, fortunately, we've got better scans, PSMA PET scans, that can find spots of cancer
even at very low PSA levels and if that's achievable, then a sequence of giving some
Provenge, maybe adding some experimental Keytruda, zapping the spot with some radiation like
SBRT, and then going immediately on a second-generation hormone therapy like Zytiga or Xtandi will
put almost 100% of men into remissions and those remissions will run, in my experience,
for many years.
So, I think one of the questions is, do you want to use sort of a full-court press or
do you want to just start a pill and ride that horse and then think about other treatments
later. If the pill starts running out of gas, then it's an even more serious situation,
you know, if the Xtandi or Zytiga stops working after a period of time, then you're on to
chemotherapy and there are fewer and fewer options. So, when in doubt, I tend to use
a combination approach.
So you mentioned with Provenge in order to be able to take that you need to have a metastatic
lesion. When they say metastatic, is that bone met or is that lymph nodes?
Any metastatic lesion. Anything outside the prostate. So, if it's lymph nodes, bone, spot
on the lung, liver, doesn't really matter. Just so that it's something outside of the
prostate.
In combination therapy, you know, that's a lot of different drugs or, you know, treatments
all at once. What types of side effects have you seen with these patients?
Oh, Provenge, the side effects are minimal. The side effects of Zytiga and Xtandi are
very similar to what people have been going through with Lupron already, so the quality
of life is good. If someone ventures down the pathway of adding experimental Keytruda
to the Provenge, then the side effects can be more notable. Men can develop diarrhea,
shortness of breath, rashes, and a variety of things that an overactive immune system
can do.
I know Keytruda is approved by the FDA in a very small percentage of men, I think it
was 4 or 5 percent of men who have a specific genetic mutation. Can you explain what that
is?
So, MSI mutation in any kind of cancer (lung, bone, prostate) it responds very frequently
to Keytruda and the results are rather amazing. It's a rare mutation. I haven't personally
seen it although we test for it in all of our patients now and that particular setting
called MSI will—the insurance companies will cover payment for Keytruda, and Keytruda
should definitely be given because the response rates are so favorable.
What tests do you do on men at your practice in order for them to test for this?
There's a couple of blood tests that we commonly use. One is called Guardant360 and the other
is called FoundationOne.
So, that leads me back to an overall question when it comes to men who are becoming castrate-resistant.
What genetic testing should a man look at early on when his Lupron stops working in
order to help enhance his treatment decisions.
Yeah, so there's another recently approved drug, Olaparib, which only is FDA-approved
for treating men that have the BRCA mutation and that is also detected with the same blood
test that we already mentioned, and men that have that mutation have high response rates
with Olaparib and Rucaparib and should get good results with those medicines, but you
have to establish that particular mutation is present. It's present in about 15-20% of
men with advanced disease.
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