Advanced Prostate Cancer
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Zytiga/Lupron/Prednisone "holidays/breaks" Anyone try this yet?

Sorry, if my posts are somewhat repetitive but I can't get answers from doctors and it's going to be months before I can get third or fourth opinion from other doctors.

Has anyone heard of "holidays/breaks" from Lupron/zytiga/prednisone combination treatment??? My doctor is suggestion this as a possibility for me. My other doctor says that once I start the Lupron/zytiga/prednisone combination, I have to stay on it permanently. Thus, It's a big decision - 1) either Lupron with intermittent "holidays/ breaks" OR 2) the Lupron/zytiga/prednisone combination with no breaks OR 3) the Lupron/zytiga/prednisone combination with breaks. Just trying to get thoughts or others with experience on these options.

Should I wait for Lupron to fail before adding zytiga and prednisone OR add the Zytiga now, before the Lupron fails???? STAMPEDE would suggest I start Zytiga/pred now but Id have to fight with insurance because my cancer isn't visible on CT scans yet (just PSMA/PET scans). I'm concerned about the lower quality of life on Zytiga too, although some mentioned that it isn't much worse for them, or not worse at all.

thanks for any thoughts you have.

George

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I tried to stop Lupron after 2 years. It lasted 6 months. Just starting to feel i was on my way back to normal. Well psa spiked to 4. Back on the shots! Five years later ...Now... Luprn failed, psa 9.8 from 3.7. just started Xtandi. Will get psa test in 3 weeks. Thats all i know.

Thomas

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good to see the Lupron last so long. what was your pre Lupron psa, gleason and doubling time?

I know the feeling about the break. I took a break after a year. It took 5 months to get my psa from .09 back up to 10.8 and then I got the new Lupron shot two weeks ago.

I'm surprised you started Xtandi prior to adding Zytiga and prednisone to the Lupron. Did you talk to your doc about this option?

George

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Pre lupron my psa was 44. Gleasn 7. My onc says she likes Xanti for the ease of use. And no prednisone.

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thanks Tjc, what was your gleason score in your cancer biopsy?

George

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Have you not considered chemo? Insurance should cover this without a fight. Trials show same improved overall survival rate improvement between chemo and zytiga. In some ways its a perdonal choice of which to do first. I chose chemo first because im 55 and there is eventually an end to your cycles. It hits it hard and then you are on lupron for maintain until castrate resistance. Then zytiga is no longer an insurance issue after castrate resistance.

But to answer yoir question, studies do show you are better of taking zytiga (or chemo) along with prednisone and lupron right away than just lupron alone. Early zytiga or chemo is the best and most aggressive care.

I have never heard of doing zytiga holidays. You are on it until it doesnt work.

I have heard of lupron holidays, but usually employed when scans are clean. I personally would never do this with existing mets in my body.

But only my opinion.

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yes, I considered chemo, Neither doctor from duke or MD Anderson recommend that for me now. I know about the studies. I think there is a bit of the docs wanting to keep my qol up and not tear me down with feeling bad for a year on chemo, so that I might gain an extra year of life. They might be thinking that my immune system and body will do better on the Lupron if my gut and immune is stronger. Plus, I have some coronary artery plaque which may play into their thinking.

Studies showed that Lupron breaks gave people the same lifespan on average in comparison to those who continued to stay on the Lupron. That's why I thought the Lupron, Zytiga, pred combo could have breaks as well. It's the same concept as a Lupron holiday in my estimation/hypothesis.

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Hi George a quick search in Pub MED produced this article, a case report. I quote the whole abstract:

ncbi.nlm.nih.gov/pubmed/294...

Oncol Lett. 2018 Feb;15(2):2669-2672. doi: 10.3892/ol.2017.7628. Epub 2017 Dec 14.

Abiraterone acetate withdrawal syndrome: Speculations on the underlying mechanisms.

Kato T1,2, Komiya A3, Yuasa J1, Kaga K1, Kaga M1, Kojima S2, Naya Y2, Isaka S1.

Author information

Abstract

A 72-year-old man initially presented with lumbar and right chest pain, but was later found out to also have an elevated prostate-specific antigen (PSA) level at 2,000.0 ng/ml. Further evaluation disclosed metastatic prostate cancer involving the bones and lymph nodes. The patient was initially treated with combined androgen blockade (CAB) with leuprolide acetate and bicalutamide. After 6 months of CAB, the patient's PSA level began to rise from the nadir (85.1 ng/ml) to 113.3 ng/ml. Bicalutamide was withdrawn in anticipation of anti-androgen withdrawal syndrome and the PSA level declined temporally. However, it increased up to 517.0 ng/ml thereafter. Consequently, a year after CAB, abiraterone acetate (AA) was initiated at a standard dose of 1,000 mg daily in combination with 10 mg of prednisolone. PSA rapidly decreased to the nadir of 20.1 ng/ml thereafter. The PSA level remained stable until 2 years after AA administration. However, he decided to reduce the dose of AA to half of the standard dose (500 mg daily). Contrary to our expectations, the serum PSA level promptly decreased to a nadir of 8.1 ng/ml. Thereafter, the PSA level remained stable until 3 years and 9 months after AA administration. Subsequently, the patient stopped taking AA and prednisolone. However, to our surprise, the patient's serum PSA level decreased further to <1.0 ng/ml after AA discontinuation. His PSA remained <1.0 ng/ml without clinical or radiological progression for 1 year after AA withdrawal. Recently, it was reported that cessation of AA is associated with AA withdrawal syndrome in metastatic castration-resistant prostate cancer, defined as a PSA decrease after AA discontinuation, mimicking anti-androgen withdrawal syndrome. In the present study, explanations of the mechanisms underlying this phenomenon were explored, including mutant AR activation by alternative ligands.

Apparently Zytiga could be stopped without ill effects in the PSA if the cancer is becoming castration ressitant, with the reservation that this article is a case report,. I'll try to get some of the references they use.

If you have metastatic hormone sensitive PC the most adequate treatment seems to be Lupron or similar plus abiraterone since it offers a survival advantage over ADT alone.

Best wishes

Raul

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Thanks Raul, that's very interesting. It seems there are going to be varying responses to the same treatments. My gut instant/analysis tells me that breaks from Lupron, zytiga, pred would work as effectively as staying on it but of course I don't have any evidence of that. One issue though, is that I don't know if I will tolerate the Zytiga, Lupron, pred combination all that well. Never know til you try. Docs are a little concerned about some 30% plaque in coronary arteries, plus, if the fatigue is worse with the combo, I might get to exercise less often due to fatique and mild depression. These are the subtle considerations we have to think about and then make a decision. Then we have to see if we can get the doc to push for our Zytiga even when my cancer hasn't been seen on a CT scan yet, only psma/PET, which insurance does not recognize.

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This is other article which seems to confirm what happened in the case report.

ascopubs.org/doi/10.1200/jc...

Is there a withdrawal syndrome with abiraterone acetate (AA)?

Laurence Albiges, Edouard Auclin, Benoit Rousseau, Elouen Boughalem, Antonin Levy, Yohann Loriot...

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Background: The withdrawal syndrome phenomenon in prostate cancer is defined as a subset of patients (pts) who experience decreasing prostate-specific antigen (PSA) values with or without clinical improvement from the withdrawal of androgen receptor (AR) inhibitors or steroids used as endocrine therapies in castration-resistant prostate cancer (CRPC). In view of its steroidal backbone and structural similarity to progesterone, abiraterone acetate (AA) might act as an AR agonist in certain subsets of CRPC. So far, this phenomenon has not been reported with AA. The aim of this study was to assess the incidence and clinical meaning of such a PSA decrease in pts after AA discontinuation Methods: A retrospective review of 218 consecutive pts treated with AA for metastatic CRPC received after docetaxel between 01/2009 and 08/2012 was conducted in two French centers. PSA values were evaluated before, during and at the end of AA treatment. We retrospectively collected PSA values performed after AA discontinuation (at 4 weeks) and until further treatment or death. Pts were typically kept on prednisone at AA discontinuation. Results: Amongst 218 consecutive patients, 66 pts (30%) were assessed for PSA follow-up after AA discontinuation; reasons for no assessment were mostly: immediate chemotherapy (13%), death (21%); ongoing AA (23%), non evaluated (14%). Amongst the 66 pts, AA therapy was associated with a PSA decrease in 65% pts. Median AA treatment duration was 5.1 months[1.5-39.9]. Twenty-one out of 66 pts (32%) had a PSA decrease when measured at AA disruption and 4 weeks afterwards. The median PSA decrease was 19% [3-68%]. A PSA decrease of greater than 50% was observed in 4 pts (19%). The median duration before progression was 5.5 weeks [1.7-54]. Two of the 4 pts with a PSA decrease>50% exhibited clinical benefit. PSA decrease duration in the 4 pts was7.1 wks [1.1-11.5]. Conclusions: A serum PSA decrease occurred in 32% of pts after AA discontinuation. PSA decrease greater than 50% was observed in 6% of pts with a potential clinical benefit. This event was usually of minor magnitude and short-term. Physiopathological explanations for this observation remain unclear and may be related to the direct activity of AA on the AR.

Talk with your doctors and mention these articles and see what they have to say. I never heard of stopping abiraterone until it fails but I never heard of this withdrawal syndrome of abiraterone. either.

Best wishes

Raul

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George,

The thing about Lupron & IADT is that T takes 6 months or more to recover, & it never comes back as high (which might not have been very high at baseline anyway). I always thought that I would opt for T replacement [TRT] in the off phases if I were on IADT.

The aim is to bypass the estrogen-dominant period, & to shock cancer cells that have adapted to low T. (Which is the point of the BAT therapy.)

TRT could be for a specified short period, such as 3 months, or until PSA reached a certain level.

One reason to try this is that it might delay resistance to Lupron+Zytiga, & extend its usefulness.

-Patrick

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Thanks Patrick, Let me make sure I understand your last sentence - One reason to try the TRT at what point? While you are on Lupron, zytiga and prednisone or if you are on an intermittent break from the Lupron, zytiga, pred combo?

It seems clear you were saying that the TRT during a Lupron only break, might be a good options for some patients.

I'll tell you one thing, from Raul's post above, the median time for AA (Zytiga) to fail using zytiga and pred (after Lupron alone failure) was 5.1 months...that sucks! Sounds like a strong reason for me/anyone to start on the zytiga/pred addition to Lupron, asap.

I really don't think one of my doctors has a strong argument to keep me on Lupron alone. He's a good, caring highly respected MO but I see a possible inconsistency in his recommendation to stay on Lupron alone and keep Zytiga as another treatment option after the Lupron fails. With STAMPEDE and LATTITUDE staring him in the face it seems logical to use all three as early as possible.

Another thing he says is that he bases everything on science and not on the art of medicine but then he tells me that he has some patients who have Lupron work for five years or more. Well, that's an anectodal observation, and he just got done telling me that I shouldn't base my decisions on anecdotal observations when I hear of people online etc who have had Lupron, zytiga pred combo working for over 10 years in some cases. His logic seems inconsistent.

I'm thinking like this: why not just try to zytiga/pred,lupron combo and see how I handle it and if I'm having bad reactions then they will reduce or stop it. After four months of the combo, if the doctor wants to give me an intermittent pause or continue it, then I follow accordingly. I just don't know where the evidence or danger lies in stopping the zytiga and starting it again later on. I have a feeling someone is going to have to do a study on this.

George

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Hi George,

TRT during the IADT break might set the clock back a bit. PSA will rise initially, but should level off. T can always be halted if that were not to occur.

With treatment mean time to failure being fairly low for all therapies used as monotherapy, I understand the mindset that wants to keep as many therapies in reserve as possible. But the mathematics favor drug combos, & the trials now back that up.

I know of a man who died in his 90's of old age, who was on Lupron for over 20 years, but the odds are very much against it. The poor guy probably didn't need to be on Lupron, & suffered 20+ years of morbity for no reason. The old studies say that failure is mostly in the 18-24 month range. There was over-use of Lupron early in the PSA era, & doctors started to say that their patients were doing better than 18-24 months. But perhaps not if they were to exclude the men who shouldn't have been on it.

Almost certainly, Lupron is my future, & I would start Zytiga & maybe Casodex at the same time. & continue with Avodart & Simvastatin, plus Metformin, etc.

-Patrick

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thanks Patrick, good message.

My oncologists don't seem to mention casodex except for the initial 3-4 weeks of Lupron period. Do you stay on it full time? Has that been shown to be better? They also didn't warm up to the idea of including Avodart into the mix. I'm on Crestor 20mg. Didn't that show similar rates of success with PCx as Zocor did? I asked one oncologist about metformin and he didn't even know what it was, which made me lose some confidence in his knowledge.

That 90 year old man...they should have at least tried intermittent or watchful waiting.

On of the other guys on this site told me his psa has been 75-120 the past few years and they think its in the nerve bundles around the prostate. This kind of surprised me because I thought that psa levels that high must mean cancer in distant locations. Ive asked him for further details.

My psa was 39 and psma/pet scans showed something that doctors thought indicated cancer in abdominal aorta lymph node and another ECE location. I've been operating under the idea that this assessment has an 80-90% likelihood to be accurate but I sometimes pray that maybe the psa of 38 is just inside the prostate but I know that's unlikely, even with a cancer that produces a lot of PSA for a small amount of cancer. The cancer hasn't been viewable on CT scans yet.

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I talked to my MO last week about the STAMPEDE trial and moving Zytiga up earlier in the treatment process. He made kind of a funny face and basically said that all that study did was allow this drug manufacturer to make more money. He said that the study didn't actually study the right thing. Rather than study Zytiga vs placebo, which of course Zytiga at any course would be more helpful than nothing, he said it would have been more helpful to see what happens between Zytiga added early and when Zytiga was added after biochemical recurrence. He continues to advocate taking each treatment to failure to try to avoid more toxicity than needed.

Regarding the suggestion of a holiday, what does your MO say is the benefit or purpose of that? Stopping Lupron doesn't immediately bring your T back up, it takes several months. I'm curious as to what he feels the benefit of the holiday would be? Just cost reduction? Or lowered toxicities? I certainly seems counter intuitive to believe that removing a treatment actually helps overall. Maybe there is a temporary further reduction of PSA, but is that really because the treatment was removed or is it because of some other factor?

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I’ve posted earlier about my response to Zytiga. The Stampede evidence is very impressive, with a greatly extended life expectancy. The figures are clear, and as a recipient myself of this regime I can testify to its efficacy. Your MO is completely wrong, he’s probably unaware of the trial interim results. Go for it ASAP.

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Tall Allen gave me a good explanation in the STAMPEDE trial. He said that about 74% of the people taking just the Lupron, did start on another kind of treatment following Lupron, either Zytiga, Chemo, Xtandi etc and that group ended up living about 18 months longer.

One anecdote from my life - I was recently, the combat vehicles requirements staff officer in the pentagon and was supposed to be the expert on the required components for all the major combat vehicles in the army. What I realized however, was that I was so damned busy with meetings, briefings, long documents and missions assigned to me, that I never had the time to get really smart on all the requirements. I'd have to cram for the test before important, high level decision meetings. Sometimes, I'd read blogs online on the weekend to bone up from people who studied vehicles as a hobby.

My point here is that these doctors have 20 minute appointments all day long and all week long and I'm starting to wonder how up to speed they are on things and if arrogance guides them to tell us the studies are nonsense. I recently asked my doctors about Berberine and Metformin and they literally said they had never heard of those items. Really?

To answer your other question - the purpose of a break is so that you can feel normal for a few months. For me the break was a little less than six months but I was back to normal for a while, could have sex, and had enthusiasm for life the way I did before the Lupron. Same concept if I could break from Lupron, zytiga, pred. Studies show that intermittent breaks from Lupron produced the same time to Lupron failure as if taking Lupron continuously.

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cfrees, check out pcf.org and what they say about stampede and latitude. pcf.org isn't the end all be all but they seem to have complete trust in the two studies and the recommendations related to the studies. They even go as far as to say that you MO might try to shy you away from the addition of the zytiga/prednisone. It could be arrogance or like someone else said, maybe they don't want to deal with fighting with the insurance companies for every patient, which requires more time on their part. Maybe they are just slow to come on board with beleiveing the study. I looked at the appendices to the STAMPEDE also and it seems that the side effects are not a lot worse for the large majority of people and there are people on this site that tolerate zytiga pred Lupron combo very well, just like Lupron alone.

best,

George

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It is my understanding that they looked at people who where given Lupron and Zytiga at the start vs those that were given Zytiga only after Lupron failed. The goal of the study was to see if getting Zytiga upfront vs waiting to it failed had an advantage.

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My understanding also. They did not compare it versus adding it, after Lupton fails.

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This is a Link to the Stampede trial:

nejm.org/doi/full/10.1056/N...

Abstract

Background

Abiraterone acetate plus prednisolone improves survival in men with relapsed prostate cancer. We assessed the effect of this combination in men starting long-term androgen-deprivation therapy (ADT), using a multigroup, multistage trial design.

Methods

We randomly assigned patients in a 1:1 ratio to receive ADT alone or ADT plus abiraterone acetate (1000 mg daily) and prednisolone (5 mg daily) (combination therapy). Local radiotherapy was mandated for patients with node-negative, nonmetastatic disease and encouraged for those with positive nodes. For patients with nonmetastatic disease with no radiotherapy planned and for patients with metastatic disease, treatment continued until radiologic, clinical, or prostate-specific antigen (PSA) progression; otherwise, treatment was to continue for 2 years or until any type of progression, whichever came first. The primary outcome measure was overall survival. The intermediate primary outcome was failure-free survival (treatment failure was defined as radiologic, clinical, or PSA progression or death from prostate cancer).

------------------------------

They compared ADT alone vs ADT plus abiraterone from the start.

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Yes! You see I also have a heart disease, and the lack of testosterone did not do that problem any good, and likely caused more harm. That and the other awful side effects were more than unpleasant. So my MO agreed. Within a year my PSA spiked up to 2; and the plan was put into place to have scans to see what was happening for my met in a rib. Well it turned out to not be a PC met in my rib, and there were no other spots that showed up! So that changed my treatment plan totally, and if I had not taken that holiday, I would still be taking Lupron for the duration. It really helps to communicate your wishes to you Doc, after all, you are in charge.

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thanks Don, glad to hear no met on the rib. Keep on truckin.

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I was on Zytiga + Pred and Lupron for 9 months. PSA undetectable for 8 of those months then stopped all hormone therapy. I continued undetectable for another 6 months then PSA slowly started to creep up. I had a two and a half year holiday from treatment before starting Eligard.

Mike

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Good info Mike. A couple question for you, if you don't mind:

- what was your PSA, gleason, and doubling time before you started the ADT (Lupron, zytiga etc)

- why did you start with zytiga, pred, Lupron then after taking a break, you did not go back to the same combo with the zytiga and pred? why only eligard/Lupron?

- where there any big difficulties weaning off the zytiga, pred? I didn't have a problem stopping the Lupron but I haven't tried the zytiga and pred.

- how did you feel on the zytiga, Lupron, pred, any bad side effects with swelling, liver, heart etc?

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Dx 1/97 - PSA 95 - GS 4+3=7 -CT Neg, BS Neg Started Lupron 1/97 added casodex 3/97, EBRT 4/97 and 5/97 - Brachytherapy 9/97 - stop Lupron and Casodex. Pretty bad hot flashes. Two weeks after stopping hormone therapy hot flashes history. Went for about 12 years with undetectable or very low PSA readings. PSA started to slowly rise 2009. CT and MRI 2/13 4 lymph node clusters positive. 5/13 start Eligard and Casodex and get 8 weeks radiation to lymph nodes. PSA still rising. 9/13 stopped casodex and started Zytiga +Pred. 6/14 stopped all hormone therapy. PSA undetectable. Hot flashes not as bad as the first course of hormone therapy. I had really bad leg cramps when I went to bed. About a week after stopping Zytiga leg cramps were almost gone. Hot flashes were nothing compared to the cramps. PSA started to climb again and started Eligard 6/17. I expect my MO will add either Zytiga or Xtandi when I see him in May.

I hope this helps you.

Mike

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thanks Mike. I wish my brachytherapy had worked like yours did.

Did the doctor say why he thought you were having leg cramps and if there was anything to stop the cramps? Does it have to do with past injuries to the leg or how old someone is. I assume from your post that you are probably in your 60s or 70s right? I'm trying to discern what side effects I might expect to have on zytiga.

george

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Would someone explain why metformin is prescribed. Is blood sugar elevated or is there another reason

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I can't answer your question but with regards to Xtandi it has been a new lease on life. Neither Lupron or Casodex were effective in lowering PSA for very long and this may also happen soon with Xtandi. But I have been on Xtandi for six weeks and I have virtually no side effects other than anxiety which is easily treated. PSA went from 13.6 to 3.1 in one month. For the first time in four years I have joy again. I no longer feel exhausted and unmotivated all the time, needing to go off and lay down several times a day. I no longer feel like I'm wearing a suit of armor every day. Xtandi has been getting a bad rap on this forum. After an orchiectomy my PSA went down to .22. I went on a holiday from casodex for four months and the PSA rose to 13.6. Since I feel so good on Xtandi I doubt that I will ever go on holiday again.

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