Making a Case for Intermittent ADT in Metastatic Hormone Sensitive Prostate Cancer

[NPfisherman]

FPC'ers,

Many times, we hear people claim that you should only stop ADT if you can't tolerate it any longer, and that it will not slow castrate resistance; that it increases risk for stroke, and heart attack; that it will likely take years for your testosterone to recover; that it increases mortality.. Let's take a look at those claims...

IADT detractors may utilize a study by Maha Hussain from 2013...... see below:

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

In this study, subjects had to have a PSA of 5 ng/ml or higher, and were given bicalutamide and LHRHa drug for 7 months, and then stopped, and continued in this manner if PSA was less than or equal to 4 ng/ml. Medication was restarted when PSA hit 20... (Is anyone doing IADT and using 20 as the restart level??). Basically, this study should not be used to consider the feasibility of IADT... Studies that rely on starting and stopping ADT based on using such numbers or bone scans or CT scans, when PSMA PET/CT scans are the new standard is deliberately deceptive.

Other studies that they may use is NCIC CTG PR.7 published in 2014, ICELAND trial-2014, and other outdated trials. What has been shown is that IADT is not inferior in outcomes vs ADT, and provide benefit from side effects of ADT... see article abstract:

nature.com/articles/s41585-....

What do we need?? Studies using the newer scans, newer meds, and the ability to ID patients that should be considered in a study. Some on this site are now on monotherapy with bicalutamide, enzalutamide, apalutamide or darolutamide, and doing well... A study that involves those options along with using SBRT in oligometastatic disease could change the current SOC... Consider this a call for new studies...

I have used IADT for 65 months now... My first treatment used SBRT plus abiraterone and Lupron for 22 months, and resulted in a vacation of 22 months for me. Opting for a shorter treatment time, I was treated for 12 months the second time... I recovered normal T in 3 months for my first treatment, and nearly back to normal after 9 months this time.

Am I stating unequivocally that IADT is for everyone?? No !!! But, for those with a less aggressive disease should give IADT some serious consideration...

As always, I welcome feedback from the forum....

DD

[6357axbz]

What triggers your stopping holiday and going back on ADT?

[NPfisherman in reply to 6357axbz]

My MO at Cleveland Clinic..

He stated we would do 2 years initially, and if I remained "undetectable", then we could stop ADT... I chose to stop at 22 months... He was not in favor of SBRT...

The second time was also an agreement between me and my MO... He asked me if he should arrange SBRT, or would I do that myself at UPMC...

What triggers me to get back in touch with him is when I go from "undetectable" on my ultra sensitive PSA... We have a follow up at that point, and I continue monitoring until my USPSA gets to a point of 0.5, so we can arrange the scan...

[6357axbz in reply to NPfisherman]

Why would you allow your cancer to grow until your PSA reaches 0.5 instead of resuming ADT when it no longer is undetectable, i.e., 0,1 or so. Just so it becomes large enough to be seen on a scan????

[NPfisherman in reply to 6357axbz]

The Pylarify scan has an increased chance of finding a tumor at that level. Being oligometastatic, I can utilize SBRT for eliminating the tumor. I timed my ADT so that my T is at a higher level for treatment, which was shown to be beneficial. After SBRT, I start abiraterone so that my T drops rapidly to finish tumor and enhance the abscopal effect.

[6357axbz in reply to NPfisherman]

But by allowing you PSA (tumor growth) to go from barely detectable (0.1) to 0.5 your encouraging the tumor to grow, just so you can see it and zap it. Wouldn’t it be preferable to go back on ADT as soon as PSA rises to a barely detectable level, thus suppressing that growth and, possibly putting the tiny tumor into dormancy? Also by letting PSA rise to 0.5 you may find you’ve allowed multiple tumors to progress and that your no longer oligometastatic.

[NPfisherman in reply to 6357axbz]

I will give an indepth answer this evening, as my wife took the laptop for her locum tenens work... Typing on the phone is tedious... At that point, I will show there is a method to my approach...

[6357axbz in reply to NPfisherman]

I’ll look forward to hearing that NP. I had a disagreement with my MO over this issue. I too am oligo. Coming off a 1 1/2 year ADT holiday when two consecutive PSA labs showed 0.1 and 0.18 respectively after being undetectable I went back on ADT. She thought I should have waited till 0.5 and do a scan.

Randy

[NPfisherman in reply to 6357axbz]

Randy,

Apologies for delay in response, the wife got back to the hotel late, and we then went to dinner ...

I am not sure why you chose NOT to follow your MO's advice. I guess it really depends on treatment philosophy. For me, my rationale was based on two things... First, by waiting, I increased the odds of finding treatable metastasis, which also would tell me my disease progression. The CONDOR study (NCT03739684), using PSMA PET with imaging agent Pylarify, reports cancer detection rates of 36%, 51%, 67%, 85%, and 97% in men with PSA levels of < 0.5, 0.51-0.99, 1.0-1.99, 2.0-4.99, and ≥ 5.0 ng/mL, respectively. I timed the scan to insure that my PSA was above 0.5. Second, I knew that I was going to use SBRT to eliminate the tumor.

I notice that you used the word, "zap", and some use the term, "whack a mole" to describe metastasis directed therapy (MDT). MDT has been proven in the ORIOLE trial, STOMP, EXTEND...

urotoday.com/conference-hig...

Please note that Dr Tang agrees with me that the outdated trial by Maha Hussain should NOT be used in consideration of IADT. Using this trial to show why people should use CADT is deceptive at best, and shows treatment bias.-from the article:

While the SWOG S9346 trial did demonstrate worse survival outcomes for intermittent ADT (as opposed to continuous ADT) in metastatic prostate cancer patients, and as such may have led to decreased adoption of intermittent ADT, Dr Tang did note that there were important limitations to this trial. Median PSA at diagnosis was notably high at 42 ng/ml, PSA did not nadir to 20 ng/ml. As such, Dr. Tang noted that he did not believe that such results can be universally translated to modern clinical practice and that these results should not lead to discontinuation of intermittent ADT regimens in the appropriate patient.

Perhaps, you have heard that "zapping mets" is just treating PSA, and provides no real benefit because of micrometastasis, or that the abscopal effect does not exist.. Even, if you do not believe in the abscopal effect, the net result is the removal of the tumor for an oligometastatic patient (me). My MO looked at it as if he were treating a patient that was "not metastatic" post SBRT since the tumor was eliminated, thus a 2 year treatment period initially.

You can choose to believe some poster, blogger, or facebook-self proclaimed expert, or you can look at the results from the EXTEND trial showing that combined therapy is better than just hormonal therapy. I like to believe in experts like Dr Tran (ORIOLE trial-Johns Hopkins) or Dr Tang (EXTEND trial-MD Anderson) versus some self proclaimed expert.

Just my 2 cents fwiw...

Dangerous Dave

[6357axbz in reply to NPfisherman]

Dave, I was part of Dr Tangs EXTEND trial. Besides RT to my prostate he subsequently, about 17 months later in October 2020, , zapped my 4 known Mets identified by the UCLA PSMA scan. I continued ADT (Lupron and abiraterone acetate) until April 2022 when I stopped Lupron. Then in July 2022 I stopped Abi. I was on an ADT holiday till October 2023 when my PSA climbed out of the undetectable range to .19. Unfortunatly I had not discussed a holiday exit strategy with my MO and I started on Abi again.

I have a fairly low PSA expressing cancer. Highest ever was 5.2. I can always take another holiday at some point and allow PSA to reach 0.5 and then get a scan and have any Mets radiated. Obviously I’m not opposed to IADT. After a long holiday I just didn’t want to allow any new cancer to grow so back on ADT I went. What’s the big hurry to get to 0.5 and get another scan? What have lost by waiting?

[NPfisherman in reply to 6357axbz]

Randy,

Apologies.... I did not know or forgot you were part of EXTEND....

Thanks for participating in a clinical trial to increase the knowledge of all.

Since prognostication is not one of my abilities, I cannot tell you how your decision changed your outcome. For me, I had excellent communication with my MO from the beginning. Post SBRT, there was an exit strategy developed at that time.... He has a number of patients doing what I am doing. Unfortunately, not all clinicians communicate so well with their patients.

I am sure you will want to explore options with your MO, and choose a strategy that you can both embrace. I do know that some people are advised on various platforms for prostate cancer that continuous ADT is best, and only use IADT if you absolutely cannot take it any longer... I can see now that was not the case for you...

Wishing you the best on your journey...

DD

[Justfor_]

The typical 70+ years old heating or air-conditioning system was controlled by an on-off thermostat. The differential between switching on and off was dubbed "anticipation". I started working as an engineer in 1975 when it was already obsolete. Too late for it's resurrection as iADT for me. Can't teach an old dog older tricks. Nope!

[GreenStreet]

I am currently doing IADT combo with SBRT and my Onco is very happy with doing it. Currently on holiday but coming up to another intervention when PSA rises to a level where a scan would be sensible.

[NPfisherman]

Hi Andy,

Glad things are going well...

I am feeling so good off the meds, and I am sure you are as well...

For me, I may choose to only do 8 months next time based on a study done by Moffitt that KocoPR I believe posted... I may be wrong about who posted it, but the idea that more (CADT) is always better is nonsense.

As we know, not all disease is the same...

All the best to you...

DD

[cujoe in reply to NPfisherman]

NP - Not sure if Moffitt still operates under this principle for their adaptive treatment approach, but I seem to remember that their PCa trial stopped treatment when PSA was halved and restarted when it doubled - the idea being to keep any one mutation from becoming dominant. The battle is between hormesis and homeostasis to dampen the survival of the fittest.

Not related to PCa, but this link provides some foundation for understanding the principles involved:

linkedin.com/pulse/homeosta...

When thinking about a heterogeneous cancer like PCa, continuous treatment of any kind seems destined to fail for all but a very select few. The more options we have and the smarter we can be in combining and sequencing them, the more mileage we can get out of the currently available treatment options.

As one of the co-founders of a CLL patient support organization says: "Smart Patients Get Smart Care™". That is a good start to staying S&W,

Ciao - cujoe

[GreenStreet in reply to cujoe]

That trial sounds like an interesting approach

[cujoe in reply to GreenStreet]

Green et al. - Here is a key exerpt from Moffitt's write-up on their 2017 PCa trial that described the cyclical treatment used in testing their Adaptive Theory. The entire write-up and links to their papers in Nature Communications and in eLife are all below:

* * *

Rather than using a conventional treat until progression approach, Moffitt researchers wanted to investigate the potential benefits of an adaptive therapy approach that bases the dose and timing of a drug on a patient’s response to therapy. They conducted a pilot clinical trial in 17 patients with metastatic castrate-resistant prostate cancer. Treatment with abiraterone was discontinued when a patient’s biomarker PSA levels decreased by more than 50% of baseline levels. When a patient’s PSA levels increased again, abiraterone treatment was reinitiated, and the cycles of biomarker testing and drug withdrawal/retreatment continued. The feasibility and clinical benefit of the adaptive abiraterone therapy was reported in Nature Communications in 2017.

In this updated analysis with four additional years of follow-up, they found that patients treated with the adaptive therapy approach had a significantly longer median time to development of cancer progression (33.5 months vs. 14.3 months) and a longer overall survival (58.5 months vs. 31.3 months) than patients treated with the standard continuous treatment until progression approach. All patients treated with the standard approach developed progressive disease and died by the time of the report, but four patients on the adaptive therapy approach still have no evidence of progression and are alive. Importantly, patients treated with adaptive therapy were off treatment 46% of the time during the trial, which can reduce drug side effects and expenses. A recent economic analysis of the study found that this could reduce the average expense per patient by $70,000 per year.

(emphasis added)

* * *

Moffitt Study Shows Adaptive Therapy Improves Outcomes, Reduces Care Costs for Prostate Cancer Patients. 29-Jun-2022 8:05 AM EDT, by Moffitt Cancer Center.

newswise.com/articles/moffi...

Integrating evolutionary dynamics into treatment of metastatic castrate-resistant prostate cancer, Nature / Nature Communications. Article, Open access, Published: 28 November 2017

nature.com/articles/s41467-...

Evolution-based mathematical models significantly prolong response to abiraterone in metastatic castrate-resistant prostate cancer and identify strategies to further improve outcomes, eLife, Research Article, Evolutionary Biology Medicine, Jun 28, 2022.

elifesciences.org/articles/...

It is a small study population, but seems to be solid proof of concept and suggests cADT may be a flawed treatment concept for most people.

Stay S&W, Ciao - cujoe

[GreenStreet in reply to cujoe]

Thanks very much for this which is most appreciated. Am working my way through it

[NPfisherman in reply to cujoe]

Dog of Terror,

Thanks for updating me.... I must admit that I have been on vacay on my reading as well... How lazy I am....lol...

DD

[NPfisherman in reply to cujoe]

Dog of Information and Terror,

Thanks for the reply... I wish I had the time and discipline to do the on/off med switch, but for me.... I prefer the consistency of scheduled dosing and then no dosing for long periods... and less labs ... to do this effectively, I would imagine that people would need to doing labs on a monthly basis, or certainly 2 months, so as not to miss windows of stopping and starting accurately...

As you say.... Be S&W....

DD

[GreenStreet in reply to NPfisherman]

Yes feeling great thanks. My holiday has been longer. There is also the worry about where it eventually pops up on a scan but I try to put that aside. So glad you are doing good.

[NPfisherman in reply to GreenStreet]

Enjoy the time... I try to not "overthink" BCR too much... it helps me mentally on my vacay...Glad for you as well...

All the best...

Dave

[NPfisherman in reply to GreenStreet]

For me, I have lost 25# off the meds...still have a bit to go... off to workout... The anemia from the meds just saps my energy...

[NPfisherman in reply to GreenStreet]

May your holiday last forever... I know a guy that did SBRT with IADT, and his holiday continues after 4 years...

[GreenStreet in reply to NPfisherman]

That’s a great result. Would take just half of that tbh

[GreenStreet]

Good for you. Enjoy your workout. Unfortunately having to take it easy exercise wise for a few weeks while medial ligaments in left knee recover

[NPfisherman]

Rest, ice, knee brace, and NSAIDs ....go easy young man...

[GreenStreet in reply to NPfisherman]

Yeah Dr was not impressed that initially I tried to run it off😂