I was discussing abiraterone acetate (brand name Zytiga) with my MO and asked why it was always given with ADT.
"I don't know, it's just always been done that way."
This seemed odd to me. ADT usually involves a drug like Leuprorelin (Lupron) to trick the hormone system into shutting down testosterone production in the testicles. But men and women make testosterone in their adrenal glands, so the levels never fall to zero.
Abiraterone acetate (AA) works more directly, by interfering with Cytochrome P450 17A1, an enzyme that is used in testosterone production in the testicles, adrenals, and some prostate cancer cells. It is called an anti-androgen.
Since AA shuts down testosterone production pretty much everywhere, at a molecular level, it seemed to me that ADT wasn't really necessary.
It turns out it isn't. Two abstracts from ACCO 2019 discuss small trials where they compared AA alone versus ADT + AA (AA is almost always given with prednisone.)
This paper describes a randomized trial with 67 patients with mCRPC. Half received continued androgen-deprivation therapy (ADT) plus abiraterone acetate plus prednisone (AA+P) or AA+P alone. In all patients, median testosterone levels remained below castrate levels throughout treatment. Unlike ADT, with AA+P alone testosterone production recovered rapidly, within 28 days of stopping treatment.
This paper describes a similar trial, retrospective rather than randomized, of 57 consecutive patients with mCRPC. 36 were treated with AA+ADT, 10 received AA alone, and 11 initially received AA+ADT and transitioned to AA alone.
Castrate levels of testosterone were maintained with all groups. The authors discussed the cost savings; in the US Lupron is roughly $1000 for a monthly dose. I found this curious, as Zytiga brand AA is about $10,000 a month. There are savings, but they are at most 9% or so.
So the combination of AA + ADT has been given to hundreds of thousands of men over the past 8 years because that's how it was done in the original clinical trials. A huge waste of time and money for lack of will or ability to think clearly about the issue.
These findings will take a while to find their way into the clinic, but I intend to discuss it with my MO at our next meeting. There are implications for those interested in integrating evolutionary dynamics into prostate cancer treatments. We can start and stop testosterone production much faster and without the need for an injection.
Interesting articles. If there is no difference in T levels, I don't see how there is a need for primary ADT if you are taking Zytiga. For those taking Xtandi, they would potentially see a bigger benefit because their T levels would rise again.
I think the problem for doctors is that all the major trials for these drugs, including chemo were done with continuation of primary ADT as a condition. So I think that's why they are reluctant.
Their malpractice...so many times they follow SOC.....why? It is established as the way to prescribe....not following that and someone has serious issues or death, and suddenly, it is the Doctor at fault....The lawyer says, "You're a Doctor, you knew prescribing guidelines, and didn't follow them. Why would you let a patient prescribe??" ....etc... It is an uncoomon MD that will go outside of SOC...
To be very specific, they did NOT say there was no difference in T levels, only that the levels were below castrate for both groups. My T was undetectable on lupron alone, yet my PSA only became undetectable when abiraterone was added. It seems to me that even when T is very low, lowering it further has additional benefit.
We know that zytiga adds to primary ADT. Specifically, there are other male hormones produced in the adrenal gland that are not blocked by primary ADT, but are blocked by Zytiga. So we know that Zytiga adds to primary ADT, but the question is: does primary ADT add to Zytiga?
Unless Zytiga drives T to zero, I'd expect lupron to lower it further. The question I've been pondering is, if Zytiga alone gives a T of 10, and adding lupron drops it to 5, is that a meaningful difference? I think it might be, but it's just a theory. I haven't followed the links in the original post, but the summary doesn't seem to answer my question.
you will see that the testosterone level is almost identical whether you add Lupron or not. Zytiga lowers testosterone more than Lupron does so Lupron cannot reduce it any further.
I stand corrected. The second link specifically states "The median testosterone concentration when detectable was 3 ng/dL in AA alone and 3.5 ng/dL in AA plus ADT", so, um, I should talk to my oncologist...
I've since heard that cancer cells have receptors for gonadotropin, which is the hormone suppressed by Lupron that signals the testes to make T. Zytiga without Lupron means you would have gonadotropin without T. What does that mean for cancer growth? Nobody probably knows, so worth further study. Hmm, wouldn't it suck if it turns out lack of gonadotropin was a risk factor
I also expect, since Zytiga is taken by the patient, that Lupron is viewed as some protection against the occasional missed dose.
The results of the exploratory study show that AA + P without continuation of LHRH therapy leads to considerable PSA response rates and longer time to PSA progression.
So abiraterone (Zytiga) alone was better than Zytiga + Lupron, at least by the measure of time to progression. There are questions that this study wasn't designed to answer, such as:
"Remarkably, experimental evidence suggests that the testosterone suppression achieved by abiraterone monotherapy is not sustained in non-castrated men and is overcome by a subsequent two- to three-fold surge in luteinising hormone (LH) levels"
The SPARE study, IIRC had older castrate resistant men with survival times around a year. Those results may not apply to hormone sensitive men living years longer. I find all this fascinating, because if I didn't, it just might get depressing
That article was written in March 2015, over 4 years ago. He discusses the SPARE trial only to note that no results are available at the time of writing. My original post linked to poster sessions from 2019, the first one discussing the SPARE trial results.
His claim about testosterone suppression failing in abiraterone monotherapy was not confirmed in the SPARE trial. Yes, those men were castrate resistant, but that affects their cancer, not the functioning of their adrenal glands and testicles.
Still not convinced. We know that after years of ADT it may take the body a very long time to recover T production if it ever does. My point is that using Zytiga only in this population for "only" a year may produce different results than using it in men for 5+ year who have never been on ADT. It might make a difference, it might not, we just don't know.
I'm quite shocked this hasn't been studied more or given more attention. At the least, I would think the health insurance companies would be all over it. With the falling price of generic Abiraterone this would be a meaningful cost savings.
I always thought if we had just one drug that effectively disables androgen receptors, then there's no need to block androgen production, because prostate cells won't be able to buy it no matter how much is available on the market. But that's my engineering thinking, biology must be more complex here. It's promising research and good find. Thanks!
The main reason why you have to take Zytiga in combination with Lupron is the FDA approval. Zytiga is approved in combination with ADT only. The phase III trial which let to this approval did compare Zytiga + ADT with ADT only. I guess the manufacturer wanted to make sure that Zytiga gets approved, so they did not take the risk and compared Zytiga only with ADT only.
However, even if you drop Lupron, the side effects are the same because they are caused by the lack of testosterone. Therefore the second trial mentions cost savings as a reason for Zytiga monotherapy.
So I wait for the results of the Embark trial which is a three arm trial which tests Xtandi in high-risk nonmetastatic PCa progressing after RP or RT. One arm tests Xtandi without ADT! This would make a big difference, compared with Lupron, because testosterone is not suppressed by Xtandi and you would not have hot flushes.
Refering to the first trial mentioned by FCoffey now, the SPARE trial. In the Zytiga monotherapy arm testosterone did not recover rapidly for all patients, just for 18% of them. However, the patients in this trial were CRPC patients which had ADT for a very long time I guess. If you use Zytiga while being hormone sensitive, testosterone may recover quickly for most patients.
Quick history. Diagnosed 2000. Radical, IMRT, Lupron, Zytiga, SBRT to an enlarged lymph node, Provenge. After Provenge and SBRT switched to Xtandi as PSA had been going up on Lupron + Zytiga/Prednisone. At that point Doc recommended Xtandi mono treatment. He knew how much I hated Lupron. I feel much better and stronger. Best of luck to you.
I had gone 12 years with zero therapy for G-9 PCa. Then had a very large jump Lin PSA, which had a doubling time of over 2 years for these 12 years.
I decided to finally go on defense and my MO’s(both) of course said Casodex and Lupron. When queried, as to why Lupron,,,simple response,,,SOC!
I elected instead to go Xtandi monotherapy with no ADT. My T jumped from 350 to over 900 immediately, my PSA fell from 374 to 10 in 3 months. Only real side effect which was of course not pleasant was intense fatigue. All other QOL systems performed remarkably well.
At 15 months Xtandi failed. Tried Lupron then, failed immediately. T at 8, PSA now climbing. Now on Cabazitaxal, had Taxotere 6 sessions one year ago. Being considered for Lu177 trial with Keytruda.
Am aware now of Xtandi trial with no ADT. Been there done that. No one has called me for my anecdotal opinion. Lol
No did not. When PSA did take a very large jump after 12 years of slowly(relative) climbing from just over 5 At diagnoses to about 70 at 12 years,,,Scan that previously always showed clean, now showed mets.
I was determined to maintain my completely normal QOL until I would be forced by progression to any seceding therapies that might compromise it. Which finally occurred 12 years plus post diagnoses. I have not a moment of regret of this decision.
Too late for any radiation to be of any value. However as noted, I chose to completely skip ADT regardless of strong recommendation from everyone and go with Xtandi monotherapy as my only systemic therapy,,,,until forced to Taxotere some 15 months later. Xtandi gave an additional uncompromised QOL,,,fatigue excepted and of course bank account,,,in those 15 months.
I’m going to give the ADT the one more year my drs want then I’m going to wake up. They don’t have a plan other than wait. Can’t imagine sleeping for the rest of my life.
The clinical trial I am involved in had me receive injections of drug degarelix (Firmagon) each month for a 3 month period. Over these same 3 months, the trial also afforded me cancer medicines to consume daily. At the end of this 3 month period, I underwent my RP surgery.
The pills I consumed 'daily' were 4 pills (1000mg) of abiraterone-acetate, 2 pills (10mg) of prednisone, 4 pills (240mg) of apalutamide and 3 pills (150mg) of indomethacin. It was quite the mix, and they kept me under close observation these 3 months (kidney, liver, blood pressure, etc.). At the end of consumption, I had surgery where the extracted prostate, LNs, etc. were taken for research.
Before I started, I asked the MO why so many different drugs are in this trial. He said it was to see how this new FDA approved apalutamide drug worked when it combined with the effects of currently approved medicines. He said that each of these medicines have their own mechanism in working against cancer. He next attempted to explain these differences to me, yet it all went over my head.
So from this talk, I don't believe one can be viewed as a substitute for another. When taken together, they could (may) provide a 'broader' range of treatment.
I have been wondering the same thing - why am I using goserelin and Zytiga for eSRT-assisting ADT when surely the Zytiga is doing all the heavy lifting?
And then today I noticed that NCT03371719 is an SRT +/- HT trial that is looking at 6 months of apalutamide… no GnRH...
So I guess this change is happening, and we just haven't been paying close attention...
The rationale for so-called ADT continuation along with abiraterone, is given in the SPARE paper [1]:
"The value of continuation of luteinizing hormone-releasing hormone (LHRH) therapy in castration-resistant prostate cancer (CRPC) remains controversial and clear evidence is lacking. Argumentation for cessation of LHRH therapy is the prolonged suppression of testosterone levels after the withdrawal of LHRH analogues and the fact that disease progression occurs despite castration levels of testosterone. Especially upon treatment with the life-prolonging cytochrome P450 17-alpha-hydroxylase (Cyp17)-inhibitor, abiraterone, which has the ability to further suppress testosterone serum levels over LHRH therapy alone, continuation of LHRH therapy seems to be negligible. However, the proven increase of luteinizing hormone levels after LHRH withdrawal, which is even further increased by abiraterone, may counteract the effects of abiraterone by the induction of enzymes of steroidogenesis. Therefore, cessation of LHRH therapy when starting treatment with abiraterone in CRPC may display an unpredictable hazard to the patients. This study will explore the role of continuation of LHRH therapy when starting treatment with abiraterone in patients with asymptomatic or mildly symptomatic, chemotherapy-naïve CPRC."
My OC at Duke recognizing I was a Sports Chiropractor and a guy who flew heavier than air machines explained that Lupron took the food away ( testosterone ) from the cancer and Xtandi stuffed a sock in its mouth....I scratched my head notified MD Anderson , they said yup we approve , got in that metal flying machine and came home...see both OC's in July...Options .....that what this site is about....Blue Skies....Grounded Sky King
My treatment is based on the stampede trial where they added Zytiga to ADT and the charts show the difference in time of failure of ADT. If you believe the trials it helped a lot for some. Some it did not help. I always wondered how they came up with my treatment and I found it in the New England journal of medicine. My guess is TalAlan could explain exactly.
Thanks for this post. I was wondering why, after 1+ years on AA+P without additional Firmagon, my T stays at castrate level. So it seemed that AA+P for those with CRPC does T suppresion AND anti-androgen functions.
When I reached CRPC while on leuprolide and bicalutamide in early 2018, I switched to Firmagon (one time), which brought my T almost immediately to castrate level. A month or so later I started AA+P. My PSA dropped to “undetectable aka <0.1, and T still castrate level even now. We’ll see how long this beast stays under control.
To those new in this group, T-suppresion traditionally is done via Lupron/leuprolide which signals the adrenal glans to tell the testes to stop generating hormone OR using Firmagon/degarelix that directly stops the testes from producing T.
Is everyone here a Gleason 8, 9 or 10 ?? THESE are guys who die from Prostate Cancer and THESE are the guys for whom treatment is difficult and becomes ineffective after a period of time..Fortunately for us, only maybe 20% of those diagnosed with PC fall into that category.
Since ADT has been "The Gold Standard" for treating advanced PC for decades, it's going to be hard to get the Oncology Community to question that or move away from it as new treatments develop..Just look at the resistance BAT is getting from the medical establishment...
I think there is 2 reasons for why GNRH agonists continue to be given in addition to abiraterone+pred. Firstly, the evidence for using ab+P is very recent (ASCO meeting, May 2019) and secondly it is published (only) as a conference abstract and it hasn't been published in a peer-reviewed journal. That is, the data hasn't been criticized formally by experts in the field. And we are aware of the conservative nature of the medical profession - not entirely without reason. R.
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