] We’re guiding you to treatment success and avoiding prostate cancer pitfalls.  I’m your host, Dr. Mark Scholz.

] And I'm your cohost, Liz Graves. 

] Welcome to the PROSTATE PROS podcast. 

] In past episodes we've covered a variety of options for men with prostate cancer.  This episode, we're going to consolidate some effective options that are not yet FDA approved. 

] Liz, as you know, we've been doing this a long time and because we only see one type of cancer, we've learned some tricks along the way.  I don't think you're going to find these things in books, or at least if you do find it in books, it's going to be mentioned in passing without much context.  I think back when I was volunteering over at USC to teach fellows in cancer, back in 1996 and Taxotere, which is one of the most effective medicines for advanced prostate cancer was just released for the treatment of lung cancer.  People were getting amazing responses from men who had lung cancer that had spread to their bones.  When I heard “bones,” of course, a light bulb went off in my head and I thought, “This might work for our prostate cancer patients.”  Indeed we found that it did.  Early reports from other practices were also showing effectiveness.  Interestingly, it wasn't until six or seven years later that the FDA finally approved Taxotere for prostate cancer.  Throughout those years, we were using Taxotere regularly with good results, but it was not an approved therapy. 

] When I was researching for this episode, it was really hard for me to find information about this.  You Google “off-label therapy, alternative medicine,” there are tons of ads you can't really figure it out, “how would I know if a lung cancer drug would work for prostate cancer?”  How do people find this information? 

] I think this is sort of insider knowledge.  There are specialists throughout the country that narrowly treat one type of disease.  They talk and they meet at meetings and they share their insights.  In a clinic where there's a high volume of patients, you can quickly determine if something actually works.  You’ll know, within a few months, usually within three or four weeks even, after you start Taxotere, if the PSA is dropping and the bone scans are improving.  It is insider knowledge and it doesn't get published unfortunately, sometimes for years.  There were small phase two trials coming out about Taxotere, but it took six or seven years before the phase three trials led to FDA approval of Taxotere and prostate cancer. 

] So this can be frustrating for patients because there are patients who are starting to run out of options, or maybe they're not liking the side effect profile and they really need to find these alternative options. 

] Yeah, of course the online forums are really helpful for patients and the internet is a great resource.  To illustrate, we've had patients that couldn't tolerate every three week Taxotere.  I remember a patient who came to me with the PSA over a thousand and we gave him a standard Q3 week dose of Taxotere, 70 mg/m2.   He just felt so terrible that he refused to take any further treatment.  We finally talked him into taking a much smaller dose on a weekly basis, which was not in the original format for the way Taxotere is used.  Quite surprisingly, he tolerated that nicely.  His PSA ended up dropping down to less than one, he had a multiyear remission, and unfortunately down the line developed colon cancer and passed away from that.  He survived his prostate cancer for many years.  So again, weekly Taxotere in small doses for men that can't seem to tolerate the larger doses is something that's not talked about much anymore, but is just as effective as getting the larger dose every three weeks. 

] What other types of drugs are you using in an off-label way? 

] Well, until recently we were using Olaparib, which is a BRCA medicine approved for ovarian cancer, but thankfully the FDA just approved Olaparib.  This is now available for people that have the BRCA mutation.  Another medicine that is, I think, widely known in inner circles in prostate cancer is a medicine called Carboplatin.  It's an injectable type of chemotherapy that's FDA approved for the treatment of lung cancer.  It synergizes with Taxotere and Taxotere’s cousin, Jevtana.  We've seen a number of men who have become resistant to Taxotere when they have Carboplatin added in small, weekly doses, couple hundred milligrams, turn around and respond again.  Quality of life is good, usually it's a weekly or every other week infusion.  So these medicines are effective, but you may not hear about them.  It's certainly not something that's quote, FDA approved and it flies under the radar. 

] Off-label drugs can be drugs used that are already approved for other cancers, or they can be drugs that are approved for a different stage of the same cancer.  Can you talk a little bit about how Zytiga and Xtandi can be used in an off-label way? 

] So both of those medicines are FDA approved for men with more advanced stages of prostate cancer.  They're both well tolerated and they're certainly effective.  It's an artifice, the way the FDA approves drugs for one stage of a disease and then refuses to approve it for another stage until studies prove that it's effective.  It's the same disease, we know it's going to be effective.  So men that have what we call High-Risk prostate cancer, in my Key to Prostate Cancer book, we talk about the AZURE stage.  These are men that have Gleason 8 or 9, PSA is above 20, or maybe seminal vesicle invasion or lymph node spread, serious cancer, but Zytiga or Xtandi, oral medicines that are commonly used for advanced prostate cancer, are sometimes covered by insurance sometimes not because it's called off-label.  These medicines are known to be effective against very advanced cancer.  Why wouldn't they be effective against an earlier stage of a more serious type of cancer?  So we often talk with our patients who are usually getting treatment with radiation and Lupron for 12 months, sort of 12 to 18 months, sort of a standard approach.  Why wouldn't we give the best available hormone medicine, which is either Xtandi or Zytiga to enhance the cure rates?  Studies are ongoing and perhaps sometime in the future, this will be the standard approach, but right now it's considered off-label. 

] So off-label drugs deviate from the standard of care.  The standard of care is how all of the insurance companies know what drugs can be paid for certain patients.  The standard of care is determined by the NCCN guidelines.  These are consensus driven management to ensure that all patients get optimal outcomes.  So insurance companies look at those and decide, “Yes, we will pay for this specific medicine and this specific patient.” 

] Yes, doctors follow these criteria as well.  The general oncologists are getting so busy with over a hundred different cancers.  They really need guidelines to know what the next step is.  If one medicine stops working, what should they do to follow?  These guidelines then become sort of like the Bible and thinking outside the box sometimes is discouraged even in clinical circles. 

] In a previous podcast episode, we talked about High-Risk prostate cancer and a couple of things that are not chemotherapy that we talked about in an off-label way are Metformin and statins. 

] Yeah, I'm glad you brought that up, Liz, because these medicines are really relatively nontoxic.  It's unusual for people to have to stop them because of side effects.  The studies that have been done aren't phase three studies, but the phase two studies that exist seem to show a big advantage.  For some reason, Metformin, which is FDA approved for the treatment of blood sugar issues, and the statin drugs like LIPITOR and CRESTOR, which are FDA approved for people with high cholesterol also seem to give better outcomes when it's combined with hormone therapy and radiation. Another issue, that's not going to come up as standard fare.  If I was in this sort of a situation with High-Risk prostate cancer, I would make sure I was taking these medicines until proven otherwise.  They're affordable and they're nontoxic. 

] One thing I did find in my research was about clinical trials.  Clinical trials can be really difficult to get into, but if you look into them and you find a drug that's being used, even if you're not eligible to use it, it can be a great place to start talking about with your doctor, because clinical trials are researching other FDA approved drugs, which means your doctor can write a prescription for the drug without you having to be involved in the clinical trial.  For those of you who are eligible for clinical trials, that's easy access to get off-label drugs.  One drug that's in a ton of clinical trials right now is KEYTRUDA, but I hear you all the time prescribing this to patients, what's going on? 

] KEYTRUDA is the miraculous medicine that kept President Carter alive after his melanoma had spread to the brain.  When you talk about clinical trials, Merck Pharmaceuticals is studying it in probably 10 to 20 different cancer types, including prostate cancer.  But Merck has been very generous in distributing this same medicine on a compassionate use basis, which means that we only have to ask Merck Pharmaceuticals for the drug and they provide it free of charge.  This is no small thing, it's a very, very expensive medicine.  KEYTRUDA is an immune stimulating medicine. It’s infused every three weeks and has activity in prostate cancer.  It’s not yet FDA approved, but we have performed our own phase two trial.  About half the patients seem to either get PSA stabilization or decline.  It's a fascinating medicine because it works by stimulating the immune system and in some patients that effect continues even after the medicine is discontinued. 

] If you want to learn more about KEYTRUDA, listen to our episode about immunotherapy.

] While we're talking about immune therapies, we should also cover Leukine, which is GM-CSF a medicine that was originally FDA approved to help people getting chemotherapy keep their immune systems strong.  Over time it was noted that some people were getting declines in PSA with this medicine.  Dr. Eric Small up at UCLA did some of the early phase two trials.  Leukine was also very popular with Charles Snuffy Myers, who is a prostate maven who retired a couple of years ago. Leukine is given by an injection like an insulin shot.  We do it three times a week and it oftentimes has no side effects at all.  It may cause some chills or some rashes sometimes, but for men that have rising PSA after surgery and are really reluctant to do hormone therapy or radiation, Leukine has achieved stabilization of PSA sometimes for years.  I don't think it will ever get FDA approved, but it is something to think about for men that have rising PSA in what we call the INDIGO category that are really reluctant to consider using Lupron or Firmagon. 

] Dr. Scholz, it sounds like you're very creative with all of this and you have a lot of experience seeing patients and offering these options, but what do patients do that can't come see you? 

] I think the safest thing is to visit a reputable university center where they're doing clinical trials.  This is where a lot of the new medicines are developed and the universities have institutional review boards to make sure that what they're doing is ethical.  The problem with the universities is sometimes they're constrained by only those clinical trials.  So if you don't fit the profile of their exact clinical trial that they're offering, they may feel a little nervous about offering you something creative, but the oversight and the professional collegiality that's at the universities generally leads to a cut above in the physician quality.  Of course they do have access to some of these new medicines that aren't FDA approved yet.    

] You can search clinicaltrials.gov to find these trials going on and find a way to search for more off-label options.  The logical next topic to follow this up with are alternative, integrative, and natural options.  But as we're running out of time, we'll talk about it on the next episode.  If you have any questions about alternative therapies, you still have time to email us before the next podcast.  You can send your questions to [email protected].  Remember to help us out by rating, reviewing, and subscribing on Apple Podcasts.  

] Hi everyone.  This is Alex with the Prostate Cancer Research Institute.  Every year we host our prostate cancer patients and caregivers conference.  Usually that is in person, but this year it's going to be virtual and free.  On September 11th and 12th we will have prostate cancer experts speaking on treatments, side effects, and lifestyle issues.  There will be live Q & A with our doctors and our helpline team, as well as awesome giveaways.   Visit our website, pcri.org to RSVP today.