It has never appeared to me reasonable that one must continue Lupron once he has submitted to Zytiga. In particular if he has a “T” level substantially below castrate level, let’s say 10 or even 5. If he can maintain this on Zytiga alone, what does ADT add?
Zytiga main action is to block the cyp17 enzyme which is critical to the production of “T” from the andrenals, testes, tumors etc. , therefore what does continuance of Lupron add of benefit to starve a PCa cell into submission.
I am aware of 60 plus years of standard of care history that just may have some impact on continuing to prescribe ADT. I suspect usual SOC philosophy plus follow the money drives much of cancer therapy medical decisions
Does anyone know of any trials or any that are planned to demonstrate one way or another that Lupron is truly required to support Zytiga’s efforts to slow or cease PCa progression?
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I too had this question on my mind . The answer I got from some is " because the clinical trials were done on combo of Lupron and Zytiga ...it became SOC.
If Zytiga blocks Androgens in all 3 sites..viz testicles, adrenals and cancer cells...WHY add on Lupron is needed ? Lets hope for an honest answer.
This has been discussed before. Hopefully, someone else will have better luck finding the thread.
However, I don't think that anyone mentioned the German SPARE study [1] (full text):
"Background
"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."
"Discussion
"There is still a debate as to whether continuation of LHRH therapy in patients with CRPC is mandatory due to lack of evidence [17]. Until otherwise proven, guidelines recommend continuing on LHRH therapy [6]. However, continuation of LHRH therapy may cause considerable side effects and unnecessary expenses [18].
"Especially in view of the current available treatment options for CRPC including taxanes (docetaxel, cabacitaxel), CYP17 inhibitors (abiraterone) and androgen-receptor inhibitors (enzalutamide), continuation of LHRH therapy may depend on the actual treatment given. With regard to serum testosterone levels, there is plenty of evidence that levels remain low after long-term treatment with LHRH agonists [9, 10, 19]. With this regard, cessation of LHRH therapy may have only little clinical relevance since serum testosterone levels remain low and may not affect proliferation of cancer cells. However, in contrast to serum testosterone levels, recovery of serum LH levels may occur after several weeks to months after cessation of LHRH therapy [9, 10, 19]. This rise in LH levels, which is even increased by abiraterone itself [12], and subsequent induction of the expression of several enzymes of steroidogenesis may counteract the proposed inhibition of intracellular androgen signaling by abiraterone. Currently, there are several clinical trials underway investigating the efficacy of abiraterone in different clinical scenarios (summarized in [17]). However, in any of these trials abiraterone will be combined with a backbone of LHRH therapy. The NCT02077634 (SPARE) trial is, therefore, currently the only trial that will give further insight into the complex hormonal changes under treatment with abiraterone with or without concurrent LHRH therapy. In case of an rPFS rate of ≤ 40% or less at month 12 in arm B (abi + Pred), further evaluation as to whether LHRH therapy has to be continued upon treatment with abiraterone in a phase-III trial is warranted. The results of the most recently published LATITUDE trial [20], showing that the addition of abiraterone to LHRH therapy in castration-sensitive prostate cancer (CSPC) leads to significant survival benefit over LHRH therapy alone, further increases the medical need to evaluate the efficacy of abiraterone treatment while sparing LHRH therapy. Becoming a new standard treatment for CSPC, the number of patients receiving the combination of AA + Pred + LHRH therapy will increase, not knowing whether LHRH therapy is necessary."
See also the reply from pjoshea13 about the SPARE trial.
My brief summary is that there are theoretical reasons to continue ADT involving leutinizing hormones, but no phase 3 trials to prove or disprove them. The SPARE trial is interesting as the advantage seemed to be with the non-ADT group, but it was a small group of old, castrate resistant men who didn't live too long and may not apply to younger, hormone sensitive men (like me) who hope to be on abiraterone for years if not decades.
So in answer to your question "Does anyone know of any trials or any that are planned to demonstrate one way or another that Lupron is truly required to support Zytiga’s efforts to slow or cease PCa progression?"
The answer is YES, and there are two small trials that show Lupron is not required.
I can report from my own personal experience that using Zytiga alone produces FAR less side effects than Lupron, or Lupron plus Zytiga. Ask me again in 3 months, but right now I'm feeling 95% better with my testosterone in the single digits for over a month than I did on Lupron, which never dropped T below 25.
Lupron messes with your brain (the hypothalmus), your pituitary gland, and the testicles. While the drug is designed to interfere with pituitary GnRH receptors, by doing so it disrupts the hypothalamic–pituitary–gonadal axis. That's the intentional part.
As far as I know, there isn't much study of whether Lupron affects other actions of the pituitary, or other parts of the brain. Given that these endocrine systems utilize incredibly minute amounts of signal molecules, I'd be amazed if it doesn't. Many Lupron side effects suggest damage or disruption of the hippocampus, which among other things is responsible for the consolidation of information from short-term memory to long-term memory, and in spatial memory that enables navigation.
As it happens, I experienced severe disruption to both of those skills, as well as other cognitive effects, while on Lupron. On Zytiga, I notice some changes, mostly because I'm hyper-vigilant, but I can still function.
So my answer to the question "Is it necessary to continue Lupron or any ADT while on Zytiga?" is not only an emphatic NO, but a strong recommendation to stop Lupron as soon as possible. You have to discuss this with your MO, but there are both studies and patients who can attest to the benefits of dropping Lupron.
As one study pointed out, it saves quite a bit of money not to waste Lupron when Zytiga alone can do the job. Perhaps that argument will convince some MOs.
It's now three months since I wrote this response. Zytiga without Lupron definitely works, and for me was a huge improvement.
Zytiga works incredibly fast. My testosterone levels dropped from high normal to single digits in one week. Talk about a down elevator! It felt like the bottom had dropped out.
It also clears out very quickly when you stop, and then an interesting thing happens. The brain, the hypothalamic–pituitary–gonadal axis, responds to the extremely low levels of testosterone by signalling for more, and more, and more. This is completely different than Lupron which shuts down that signal path.
The testicles also get the message, and do their damnedest to make more T. They can't, because the Zytiga disrupts an enzyme crucial to the process, but the testes don't know that.
Mine shrunk quite a bit on Lupron. I figured it was permanent. But after a few months on Zytiga they had grown noticeably, almost back to their former size.
When the Zytiga is halted, all of that formerly blocked production resumes with a vengeance, and testosterone levels shoots up before settling back to more or less normal values. It takes a while for the body to get back to a stable place, but it does.
The doctors who reported on small clinical trials seemed surprised at this, and even sounded a note of caution. I laughed, these guys have no freaking idea about basic control and feedback loops! This should have been anticipated.
I don't see any harm at all in a temporary surge, so long as the cancer has been controlled by the time on Zytiga.
There has been a small, non-randomized study that found: "The authors here examine the ability of abiraterone to suppress testosterone alone without leuprolide. This was a non-randomized study with a very small cohort of patients, but it nevertheless provides thought-provoking data regarding the use of abiraterone alone without the addition of leuprolide. For this practice to shift to the standard of care, larger randomized studies are necessary to demonstrate that ADT + Abiraterone is equivalent to Abiraterone alone. "
I had brought this question up at last evening’s support group meeting of some 35 members of our so called “advanced” group,,,several on or have been on Abiraterone.
I knew that some months ago that I had read if or not ADT was really required to continue when submitting to Zytiga,,,this was a point of curiosity with me, just as now,, is Prednisone really required when on Taxotere or Jevtana,,,which I am currently on.
I was asked of any references on my assertion that perhaps ADT not required with Zytiga. I can now report back these references.
Today one our members will be seeing Dr. Turner today. He will be asking him his opinion and does he still require Zytiga patients to maintain ADT.
The other biggie now of course is the newer findings on the possible effect that perhaps even very short time use of hormone deprivation(via medication or castration) may have on future Alzheimer’s and/or dementia diagnosis. That too was brought up by me,,,definitely got a lot of sleepy heads at the meeting to suddenly pay attention.
There is not definitive data showing overall survival is similar with Abi+prednisone+lupron vs Abi+prednisone. The SPARE trial (67 patients) concluded:
"Conclusions: Results of this exploratory study suggest that treatment with AA+P without ADT may be effective in patients with mCRPC and that ADT may not be necessary in patients receiving AA+P. In some patients, serum-testosterone levels may rise rapidly upon treatment discontinuation so that the levels should be monitored closely".
It was interesting that both groups had the same level of testosterone at the end of the study.
One can get the same reduction in testosterone using only Zytiga. If that is true, then ADT to suppress testosterone produced by the testis may not be needed.
T=T. From my layman’s eyes, only if the addition of Lupron would bring ‘T’ level below that achieved by Zytiga mono-therapy, I see no advantage at all to the addition of Lupron,,,,unless magically it was found that the Lupron medication has a yet undiscovered ability to directly attack and compromise PCa cells.
Some have mentioned that if you were for some reason to cease Zytiga that Lupron would be your backstop.
One could always once again submit to Lupron injections before Zytiga was ceased in order to maintain castrate levels.
Ceasing Zytiga should just as ceasing Lupron,,,normally should take days before ‘T’ levels begin to increase.
I was on both early. This was a constant source of disagreement between my urologist and oncologist. Urologist said wait on the Zytiga until more cancer shows, while the oncologist said the more the merrier. We're just waiting now.
My oncologist had me on Zytiga and ADT intermittently for several years, but stopped giving me the Zytiga the last time he gave me ADT. The oncologist who took over for him when he was promoted, only has me taking ADT and I am on a continuous course ADT of it now. She is willing to have me also take Zytiga but, in her judgment thinks it's better that I don't at this point.
When she says that in her judgement it's better that you are not on it at the same time, does she also say why she believes that? I got the impression from my doctors that if they used it once and the cancer became resistant, then they wouldn't go back and try it again, obviously. I feel like I'm playing Russian Chess. If they move and lose a piece, then someone shoots me in the gut and we keep playing till I've got nothing left.
Yes. 1) All these drugs have significant side effects and should be avoided when possible. 2) The study showing people did better with Zytiga and ADT failed to compare people who had ADT AND THEN had Zytiga when the ADT failed. So, I think she wants to keep the Zytiga for use after ADT fails.
I stopped Lupron 10 years ago. T levels almost zero because I was on Ketoconozale and T never rose after that. Why do Lupron? Using an estrodiol patch for the hot flashes, and in a small way, that is my lupron. Patch also helped me with memory, joint deterioration, osteoporosis, and overall helped me feel better. Now on Zytiga + prednisone. Doing a half patch. No Lupron.
I came across these two posters from this years ASCO conference. While not definitive, they seem to suggest that Abi alone can adequately maintain Low T just as well as ABi +Lupron. Also the other poster suggests that the monetary aspect of ADT injections is an issue along with questionable additional clinical benefit. see poster session 5046 and 5049
I asked this question to my Uro, who’s administering my Lupron and he said let’s follow the Stampede guidelines, and stay on L + Z. I was on Z about 3 weeks before L, and it was a breeze. Adding L gave me night sweats, sluggishness, and some weird dreams, especially the first few days after a shot. My goal is to minimize SE’s while still maintaining PSA <0.1 and T < 10. So I decided to reduce dosages of both, 1/2 dose of Z, and a monthly L injection every six weeks. So far, tests are good. I am taking Z with some yogurt, so that probably bumps the effective dose up to 3/4 to 1/1.
There exists another option which I chose. That is monthly 1/2 dose shots of Lupron. Is a common approach in Japan, perhaps other countries.
Within 2 months my ‘T’ dropped from almost 900(I had been on Xtandi monotherapy and ‘T’ had doubled) to between 6 and 8 after 1/2 dose injection of Lupron and remained there.
Unfortunately I was castrate resistant already after 15 months of Xtandi,,,,therefore with almost non-existent ‘T’ my PSA still continued to climb on Lupron.
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