Some readers will already have seen headlines like this one from The Vancouver Sun and/or this one from Fox News (which originally seems to have come from The Sun in the UK). There is inevitably excitement around such news reports, and it needs to be said that the concept of “bipolar” cycling of high and low levels of testosterone has been around for a while, but these new data may be the stimulus needed for large, randomized trials of this type of therapy in carefully selected groups of men with advanced forms of prostate cancer.
As yet, unfortunately, we have not been able to identify the original press release that has to be the source of this story, but here is what we currently know.
The data come from an ongoing Phase II study called the RESTORE trial, which is being conducted here in the USA and is led by Dr. Samuel Denmeade at Johns Hopkins in Baltimore. “RESTORE” stands for RE-sensitizing with Supraphysiologic Testosterone to Overcome REsistance. The way this type of treatment works is by use of a technique called bipolar androgen treatment (BAT), in which the patients receive treatments that can rapidly lower and raise testosterone levels by alternating the use of androgen deprivation alone and testosterone supplementation while ADT continues. We had mentioned the development of this trial in an earlier commentary back in 2015.
What seems to be “different” about the RESTORE trial as compared to earlier forms of BAT is that it is being used in men who are castration resistant and who have already progressed after initial treatment with either abiraterone or enzalutamide. The men in the RESTORE trial who meet the entry criteria are all on standard forms of LHRH agonist therapy (e.g., Lupron or Zoladex or similar); they are then being treated with intramuscular injections of testosterone (either testosterone cypionate 400 mg or testosterone enanthate 400 mg) every 28 days. When they progress on testosterone cypionate or enanthate, the men are then retreated with daily doses of either abiraterone 1000 mg daily or enzalutamide 160 mg daily, depending on which drug they had received before.
According to the data presented by Denmeade at the meeting in Munich:
- 47 patients have been treated to date.
- All 47 patients seem to have received at least three cycles of treatment.
- 6/47 patients (13 percent) tested positive for a protein called AR-V7 prior to BAT.
- PSA levels
- Decreased significantly in about 40 percent of all the men in the trial
- Decreased by > 50 percent in about 30 percent of men in the trial
- 1/47 patients (2 percent) had PSA levels that dropped to zero after 3 months and remained at zero for 22 cycles.
- All 6 patients who were AR-V7-positive prior to treatment were AR-V7-negative after BAT.
- With respect to side effects,
- 1 patient reported an increase in pain.
- 1 patient reported a problem with urine retention.
The RESTORE trial seems to have originally been designed to enroll 30 men who had CRPC and had progressed on abiraterone acetate and another 30 men who had CRPC and had progressed on enzalutamide. So the data presented by Denmeade in Munich are preliminary.
What Dr. Denmeade is actually quoted as saying is that:
I think we may have cured one man whose PSA dropped to zero after three months and has remained so now for 22 cycles. His disease has all disappeared.
However, Dr. Denmeade also pointed out that:
We are still in the early stages of figuring out how this works and how to incorporate it into the treatment paradigm for prostate cancer.
and
Some men also have objective responses with a decrease in the size of measurable disease, mostly in lymph nodes. Many of the men have stable disease that has not progressed for more than 12 months.
There is already a newer, ongoing, randomized, multi-center trial in the US that is comparing BAT + enzalutamide in men who have become resistant to abiraterone acetate. This is the so-called TRANSFORMER trial that is scheduled to enroll a total of 180 participants. Dr. Denmeade is the lead investigator for this trial too. At present, Johns Hopkins is the only center that is enrolling patients.
Of course one of the really critical questions is whether forms of BAT can be used much earlier in the disease to arrest progression before a patient becomes castration resistant at all. We’ll probably need to see how patients do on the TRANSFORMER trial before anyone is going to be willing to look at that opportunity. In the meantime, “One swallow does not make a summer”, but the first swallow each year gets a lot of people excited (your sitemaster included).
Filed under: Living with Prostate Cancer, Management, Treatment | Tagged: advanced, androgen, BAT, bipolar, Treatment |
THE "NEW" PROSTATE CANCER INFOLINK 
I truly believe we are seeing the beginnings of a paradigm shift in the treatment of prostate cancer, as well as the role of testosterone (T) levels , and the whole understanding of the relationship between T and prostate cancer.
Thank you Sitemaster for this report.
I re-read the original 2015 abstract about BAT and the underlying graphs and charts so I could try to understand how super-amounts of testosterone (testosterone injections that raised serum levels on average to the 600s) could actually result in a decrease in PSA and tumor size in some patients; a counter-intuitive proposition. Here is my layperson’s understanding of the theory:
It appears certain prostate cancer cells undergo biochemical changes or mutations when they are deprived of testosterone for a period of time (or they mutate over time regardless of testosterone deprivation). With respect to those cells which mutate because of low T levels, the cells develop the ability, through ligands and over-expression of the AR receptors, to live and grow on very small of amounts of testosterone in the deprived testosterone environment; thus the observed rise in PSA with castrate levels of testosterone. Second-line hormonal therapy drugs like enzalutamide and Zytiga attack these ligands and over-expressed ARs, which may result in PSA decline or stabilization in the castration-resistant state.
When super-amounts of testosterone are injected into the muscle of patients in the castration-resistant state, these now super testosterone-sensitive prostate cancer cells take in so much testosterone that some of the cells die from testosterone “overdose”: ligands are broken, DNA strands are destroyed, and other changes in the cell occur, including those involving AR-V7. Further, if some of these super-sensitive prostate cancer cells survive the onslaught of testosterone, they become hormone sensitive again and can be re-treated with standard ADT. Ah, the mysterious nature of prostate cancer cells ….
If my simplistic understanding is correct, it would seem that castration resistance is a condition precedent to successful BAT, and BAT may not be very useful in an earlier stage of the disease (for most patients — but there are always exceptions). This discussion assumes, of course, that successful BAT will lead to longer prostate cancer-specific survival, in addition to better erections while on the therapy :-).
Am I out in left field here??
Best regards,
Richard
One aspect we do not know, is how durable BAT will prove to be. Sitemaster … are you aware of any information on this?
We have one guy from our virtual advanced support group, living in Idaho, whose med/onc has put him on a replica protocol. I believe Dr. Mike Schweitzer at the University of Washington Seattle Cancer Center, another lead researcher in the same RESTORE trial, provided guidance; Seattle Cancer Center is also recruiting. We have a couple of other Johns Hopkins patients considering BAT.
Richard: Your proposed explanation of how BAT works makes theoretical sense, but my gut feeling is that this is all biochemically far, far more complicated. I think it is going to take us a while to work out the implications.
Rick: As far as I am aware the RESTORE study is the only study that has given us any long-term data at all on the effectiveness of BAT. It will take at least the TRANSFORMER study above-mentioned to tell us whether such therapy is having any meaningful impact on patient survival.
We spent quite a bit of time last night discussing BAT, both with the gent who is in process and with one of our regular participants, Dr. Bill Burhans, who is an advanced prostate cancer patient on olarib, a drug he has researched personally, and a cancer research professor at Roswell Park. You can find the recording here — the conversation starts around the 90+ minute mark; it follows our discussion on [11C]acetate scans.
Two points to make here:
(1) Bill explained the activation process much the same way as Richard Stanton — essentially, the starved androgen receptors are overwhelmed and OD — a good term, Richard.
(2) I can clarify the protocol that “our” guy is following. He is doing 3 x 28 days cycles; in the first 14 days he gets a high dose of T. and etoposide; in the second 14 days, he gets nothing. Bill explained that in general the etoposide disrupts the DNA replication, supporting cell death from killing off the ARs. So Mike, you are correct — however, Schweitzer/Seattle Cancer Center are also working on BAT trials.
O&U, rd
These stories seem to be based on Dr Denmeade’s presentation at the recent symposium on Molecular Targets and Cancer Therapeutics in Munich, the abstract of which can be found here
As Sitemaster notes, the idea of treating prostate cancer with high doses of testosterone has been around for awhile. Dr Robert Liebowitz in Los Angeles has long been an advocate of this idea — the video lectures on his website make interesting viewing. But he seems to have found few followers in the medical community. Some well-done trials would be most welcome.
I think Abraham Morgenthaler may well be the source of Liebowitz’ protocols. Here’s a recent meta study co-authored by him.
Dear Rick:
Abraham Morgenthaler certainly has been one of the most outspoken about the role of testosterone and whether its use does or does not increase risk in certain types of patient. However, … that doesn’t mean that an awful lot of other people haven’t been thinking about it and studying this rather less loudly in the background.
Is there a site I can go to to get current information?
Dear Herschell:
As far as I am aware, this is the most current information available.
If you want to hear about BAT from the horse’s mouth, please listen to our Answer Cancer Foundation presentation by Dr. Sam Denmeade of Johns Hopkins made in February 2017. You’ll find it on our website.
Thank you