Xtandi and Intermittent

[Domas]

I started Xtandi 2 months ago and got PSA undetectable. <.001. Now, my doctor suggest me to reduce from 4 tablets per say to 3 tablets per day. A month ago, I say "no", reasoning that reduction of the amount may create an early resistance to Xtandi. But he is persistent. He said no necessarily. Reasons are:

1. Cancer cell will evolve anyway to overcome Xtandi in many cases in respect to the dose.

2. 4 tablets may have overwhelming side effect, and the current 4 tablets looks to him is overdose. 3. The intermittent application of Xtandi may prolong the Xtandi. for example, I can use it for 4-10 years as opposed to 2 years, assuming that it will not create "resistance".

He asks me to make a decision on 4 tablet vs. 3 tablets. Why do I have to make a decision? I am a lay person... I don't know what to do. I talk to my sister, who is a pharmacist. She said in most cases of antibiotics, if you increase and decrease frequently, it will create a "resistance", but she said she has no idea whatsoever in case of "hormone therapy".

Is there any Xtandi user here who is intermittently using them? The doctor also mentioned that I have to go through with "vacation" from time to time.... which means "no Xtandi" for a couple of months from time to time. I am literally scared. I need your advice and help..... Thanks.

[Justfor_]

You are a lucky guy to have a doc that uses their brain instead of the typical pharma cookbook. <0.001 in two months proves that you have an exeptional sensitivitity to the drug.

More is NOT better. We Greeks know it since the 5th century BC.

I have been taking the minimum efective dosage of Bicalutamide for 32 months now.

healthunlocked.com/prostate...

[MooseJawg]

I was on 4 tablets in Nov/Dec with strong side effects. Reduced to 3 since. Still some side effects but fewer and not as strong. Everything holding stable with no increase and decrease in PSA from 25 to 15.

[Tall_Allen]

Your doctor is an idiot, and I suggest you find a new one. Ask him what evidence he has for what he suggests.

1. While it is true that cancer cells will eventually evolve to become resistant, the evolution comes faster if you reduce the dosage. Unfortunately, you have used bicalutamide, which is known to cause earlier resistance and there is cross-resistance between anti-androgens.

2. Most men do not have a lot of side effects from Xtandi at the recommended dosage. Since you have already have been taking it for 2 months and tolerate it well, there is no problem. If it ain't broke, don't fix it.

3. Intermittent use can create resistance, just like an antibiotic. Your sister is right. By stopping and restarting, you may be selecting for more resistant cancer cells.

[Schwah in reply to Tall_Allen]

TA, everything you write generally has science to back it up. However, I am not aware of any study to back up your # 3 statement that “Intermittent use can create resistance..”. I was under the impression that there are no current studies out there that imply intermittent use of drugs like Xtandi and Zytega, lead to resistance any faster (or slower) than continuous use. Am I missing something?

Schwah

[Tall_Allen in reply to Schwah]

The OP is already castration-resistant due to substandard use of bicalutamide. Intermittent ADT is never used on castration-resistant men. We know that castration resistance involves the amplification of the androgen receptor and sped-up genomic mutations that allow resistance to hormone therapies. That's why ADT is always continued continuously and why Xtandi and Zytiga are used until they stop working, never intermittently. You are right that it has never been and will never be the subject of a clinical trial because we already know it can harm patients.

[Schwah in reply to Tall_Allen]

If you are talking about castrate resistant men, I would agree. But as I’m sure you ate aware, many well respected oncologists support hormone sensitive men taking “vacations” from both ADT and zytega (or Xtandi) under the belief that such vacations do not negatively impact their patients long term survival. I for one am on month 26 of my second vacation with a slightly declining PSA and clear PSMA scans.

Schwah

[Tall_Allen in reply to Schwah]

The OP is castration resistant, and I was responding to him, not you.

[CousinGrandpa in reply to Tall_Allen]

TA, have you reviewed the EMBARK trial info? It is based on 9 months of Lupron and Xtandi followed by a "vacation" if the PSA drops below 0.2 ng/nL.

pubmed.ncbi.nlm.nih.gov/371...

[Tall_Allen in reply to CousinGrandpa]

Yes, of course I have:

prostatecancer.news/2023/05...

But that is not relevant for the OP.

[thor17 in reply to Tall_Allen]

FYI Adaptive therapy aims to control cancer spread rather than try to eliminate it completely. The dogma for the last 50 years in cancer treatment has been that you apply the same drug, or combination of drugs, in cycles, until there is clear evidence of tumour progression (where the tumour begins growing uncontrollably) or excess toxicity, says Gatenby – which is usually well after the maximum response has been obtained. This is "futile", he says, since the majority of the cells left are resistant to the drug and by continuing with the same therapy, the oncologist gives them the opportunity to proliferate so their population gets larger and more diverse. His theory of adaptive therapy, by contrast, aims to tweak the dosage of drugs for a tailored approach, just giving enough treatment to knock the tumour down, keeping it as small as possible, without eliminating the sensitive population completely. Then the therapy is withdrawn. This allows the cells sensitive to treatment to continue jostling for space within the tumour, preventing other drug-resistant cells from dominating due to an adaptive advantage.

"Since we can't control the tumour cells that are resistant to therapy, we need to recruit the treatment-sensitive cells to do it for us," says Gatenby, who has been developing the idea since first publishing on it in 1991. "You can just keep treating it in cycles and just keep knocking it down and letting it grow, knocking it down, letting it grow." The hope, he says, is that doctors can keep patients alive for a long period of time, about half of which they don't have to deal with the side-effects associated with the treatment.

His research group, which is arguably the most advanced in the field, have already shown this technique works in a small pilot trial involving patients with prostate cancer. Patients who underwent adaptive therapy received half the normal dose of a chemotherapy drug over the course of the trial, during which they spent 46% of the time receiving none at all. The time from starting the therapy to when the cancer stopped responding to treatment was 19 months longer in the group who received this adaptive therapy compared to those who underwent the standard course of chemotherapy. The patients who had adaptive therapy also had an overall survival that was 2.26 years greater than those on the standard treatment.

[thor17 in reply to thor17]

moffitt.org/inspiring-stori...

[Justfor_ in reply to thor17]

I have emailed Dr Gatenby my self experimentation with Bicalutamide dosage adjustment and his response was that they had tried something similar to mice only to get surprised by the fact that lower and lower dose was needed with time. This is exactly what I have noticed in my case. I was at 1/10 of normal dose and started getting PSA readings of <0.01, thing that made me change lab to dig down to the 3rd decimal place, Dr Gatenby aslo informed me that all mice in the trial died of age and not cancer. Fingers crossed...

[Tall_Allen in reply to thor17]

The OP is castration resistant so your comments do not apply, but I will respond anyway.

Gattenby published a small uncontrolled trial of 16 asymptomatic mHSPC patients. They all received ADT+abi/enza. Vacations were given if they responded and lasted until PSA progression. Median follow-up was 26 months. Of those, 2 had radiographic progression within 28 months, 2 were castration-resistant at 12 and 21 months, and 11 restarted ADT within 6 months. Only 2 patients were able to go more than 1 year without restarting ADT, and they were both "low risk."

ncbi.nlm.nih.gov/pmc/articl...

So are there some patients who could benefit from adaptive therapy? Impossible to say. EMBARK, PRESTO, also show that for recurrent non-metastatic men, a limited term of ADT+ARSi prolongs progression-free survival on vacation. SATURN also used limited-term hormone intensification and MDT on oligometastatic recurrent men detected with PSMA PET/CT.

More interesting (at least to me), Gattenby also did a pilot trial of intermittent vs continuous (SOC) abi in 33 mCRPC patients. ADT was continuous in all. None had received abi while they were mHSPC (which is now SOC). Overall survival was 59 months for the adaptive therapy group vs 31 months for the non-randomized control group. In the STAMPEDE trial that gave continuous abi+ADT to mHSPC men, overall survival was 77 months (vs just 46 months for ADT alone). So men are clearly better off with continuous full-dose abi+ADT up front compared to adaptive dosing after castration resistance sets in.

ncbi.nlm.nih.gov/pmc/articl...

[Domas in reply to Tall_Allen]

Am I Castration-resistant prostate cancer (CRPC)????

I do not think I am Castration-resistant prostate cancer (CRPC). CRPC is defined as a type of advanced prostate cancer that continues to grow even when testosterone levels are low. My testosterone level has never been below 1,000 (throughout my entire PC period) since 2017 until 2-3 months ago when I took Zoladex injection. 2 months ago, Zoladex injection gave me testosteron level of 23, and 1 month ago, I have 28 (testosterone).

I need a help from my colleagues to find if I am a Castration-resistant prostate cancer (CRPC).... please.

[Tall_Allen in reply to Domas]

Unfortunately, castration-resistance (or, in your case, hormone therapy resistance) also occurs when PSA increases in spite of the androgen receptor being blocked, in your case, with Casodex (bicalutamide). When the androgen receptors are activated, the cancer cells reproduce and multiply. They can be inactivated by depriving them of testosterone, either via physical castration, chemical castration, or anti-androgens. PSA increases because the androgen receptors on your cancer cells got activated in spite of Casodex. Serum testosterone increases on Casodex because testosterone has nowhere to go. The reason Casodex isn't used much anymore is that drugs like Zoladex are much more potent at preventing activation of your cancer's androgen receptors.

Several trials have proven that hormone therapy intensification with second-generation drugs like Zytiga, Xtandi or Erleada prevent castration-resistance longer.

[Domas in reply to Tall_Allen]

Isn't it true almost everybody is using bicalutamide for a few years before they use Xtandi? If so, almost everybody is Castration-resistant. Right?, because the PSA increased in spite of the androgen receptor being blocked, in your case, with Casodex (bicalutamide).

[Domas in reply to Tall_Allen]

I need a help!!

Can you introduce a medical doctor in New York area, I will seek for a secondary opinion regarding the issues:

(a) intermittent application of Xtandi is harmful or beneficial in my case; and

(b) if I am a castration-resistant PC due to substandard use of bicalutamide.

[Tall_Allen in reply to Domas]

Try William Oh at Mount Sinai, or Howard Scher at Memorial Sloan Kettering.

[JJFR60]

I went from 4 (160 mgr ) to 3 (120 mgr ) .

Psa still went down/ was stable for 5 years with less side effects.

Listen to your doctor!

[BigTom123]

You'll be fine. The Xtandi does negative things to your body. Cut the dose, monitor your PSA and take your "vacation.!"

[tarhoosier]

I am 18 years out from surgery for G ( 4+5). I started Xtandi in 2014 at full dose with degarelix. After a year of both I went off treatment for 10 months then started Xtandi 4/day. After a year I went to 1/day. Then a year later 2/day and a year later 4/day all to reduce psa to near zero. Last year after RT to a spinal met I went to 1/day and continue with very low psa. My MO agrees that I can make this decision as an educated patient. Normally he would not reduce dose unless side effects suggested to do so. He made no comment about dose affecting resistance.

My response is not normal. I relate it here as anecdote.

[larry_dammit]

wow. New one on me. I’ve been on the 4 tab now since Dec of 2016. So 7 1/2 years. Yes I’ve had side effects but nothing unexpected. Main thing is no opioids because the cause neuropathy on me. Keep up the fight warrior

[Kanchenjunga]

There is a report on low dose enzalutamide for over 4 years. This case is 84 years old, now 87 years, treated 25% (=1 Cap) of the recommended dose (=4 caps, 160mg). The result is Nothing extraordinary happened. The desease responded without dramatic toxicities. Refer to: PMID: 33657823, DOI: 10.48095/ccko202169, G Gilles Natchagande, Vincent Vinh-Hung , Ecerpt from: PubMed

[MooseJawg in reply to Kanchenjunga]

Proving once again there is a lot we don’t know plus each patient is different in some way.

[j-o-h-n]

Yep the good old summer time controversy.........summertime it works, summertime it doesn't.

Good Luck, Good Health and Good Humor.

j-o-h-n

[billyboy3]

well to throw water in thus, I have lasted 26 years on IHT using lupron and casodex and durestide.

Now the casodex appears to have caused my psa to skyrocket so time stop it and add zxtiga/pred and see what happens.

[Blackwildhorse in reply to billyboy3]

Have you ever checked testosterone number since 26 years ago?

[billyboy3 in reply to Blackwildhorse]

Yes I very do often never went beyond 3 until the major break they when it went to 9 last November!

I should add that I could still have erections and orgasms until say may of this year do a huge benefit if IHT !!!

[Brendan1904]

Hi Domas, Not sure I can really help. I was on Xtandi for over 2 years, 4 tablets every day. My PSA never got below 30+, so no option of reducing dose. I trusted my doctor and that they always recommend what they calculate is best for me using their expertise. If you can trust your doctor go with it. If not then try and find a specialist you can trust.After Xtandi failed last December I had 6 sessions of Docetaxel which began to fail in June. Now waiting to see if anything else recommended by Consultant next week. Since stopping Docetaxel 7 weeks ago I had 2 days bad diarrhea followed about week later by COVID at beginning last week. 4 days flat out with COVID felt worse than last 3 years cancer. I was heaving badly but rarely actually sick. Tested negative to COVID beginning of this week but recovering only very slowly. Started eating a little again after the 4 days.

Not sure this helps with your decision but whatever you decide try and avoid getting ill with anything additional.

Good luck and keep optimistic.