Metastasis Directed Therapy (MDT) is here to stay for Oligometastatic Patients !!! Part(1) SABR/SBRT

[NPfisherman]

Greetings FPC Members,

Metastasis Directed Therapy (MDT) is becoming a standard of treatment in oligometastatic patients. Some posters will say,"Well, I guess you can do SBRT to mets...it likely won't hurt...", but this is far from the truth... It is much more likely to BENEFIT you with a low potential for toxic events...

Today, I will present some papers, studies, etc. to show the value of MDT in oligometastatic patients currently, and discuss where we are headed in the future. The first paper reviews some of the studies done and trials ongoing.

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

Next, we take a look at the STOMP trial, which stood for Surveillance vs metastasis directed Treatment of OligoMetastatic Prostate cancer. The study evaluated surveillance vs metastasis directed therapy and ADT was given with progression.

ascopubs.org/doi/10.1200/JC...

oncology.medicinematters.co...

STOMP showed that:1)the safety of MDT was excellent, with no grade 2 or higher events and only 17% grade 1 toxicity, 2)The primary endpoint of ADT-free survival was achieved by 34% of the MDT group and 8% of the surveillance group over 5 years, a significant difference that correlated to a hazard ratio (HR) of 0.57 in favor of active treatment. 3) Men who received MDT had a reduced likelihood of developing castration-resistant prostate cancer.

The ORIOLE trial went further by not only looking at SBRT in oligometastatic prostate cancer, but by looking at the T cells and variation for immune response under the microscope. It also evaluated for treating all lesions that could be found using the best current scan, the Ga 68 PSMA scan versus those not fully treated. Finally, it took a look at genetic mutations and how that was involved with recurrence. From the article below: The effect of radiotherapy on the immune system is also an area of interest with the promise of using SABR to induce an in situ vaccine response.20,31 We observed enhanced differential clonotype expansion, clusters of similar expanded T-cell receptors, and a clinical benefit to greater baseline clonality seen only in participants treated with SABR. (Abscopal Effect). SABR treated patients that had no major mutations also had a prolonged progression free survival. From the conclusion--Although SABR alone may or may not be sufficient as curative management, the combination of SABR with systemic therapies may provide the multipronged attack required to cure this disease.

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

But where is MDT headed regarding SBRT?? I believe we will see more trials involving combo therapy--Systemic therapy with SBRT and Xofigo is currently on trial at City of Hope. The RAVENS trial with SBRT and Xofigo is ongoing and expect some interim data in 2022. Trial for abiraterone and apalutamide for 6 months with ADT and SBRT is ongoing and will have initial completion in July of this year--see below:

clinicaltrials.gov/ct2/show...

A video on SBRT and oligometastatic disease...

youtube.com/watch?v=jU7cOhL...(Not working as expected?)

Some may add that there is no proof of overall survival benefit, however, they leave out a key fact in that statement. A Phase 3 study will have to be done over 10 years in OM PCa and there are numerous challenges involved in studies of this length including people dying from cardiac events.... SABR COMET 10 is a Phase 3 trial and if there is a benefit for 4-10 lesions then 1-3 lesions is pretty much a given....

Don Pescado

[cesces]

Sometimes you have to deal with imperfect information.

It seems to me that this issue isn't whether sbrt works on the mets you can find.

The issue is what to do about the ones you can't find.

Do you hit them globally with systemic treatment or wait until you can find them.

So I would submit that the decision to use localized treatment on mets you can see, is a separate decision from the use of a systemic treatment.

There is no law against using both by the way.

[NPfisherman in reply to cesces]

Not only is there no law in using both... I advocate using both in oligometastatic patients (if safe treatment location)... While some of the trials focused on delaying ADT, the trials that I am watching are some of the ones that I listed....RAVENS, the City of Hope trial with ADT plus SBRT plus Ra223, the trial with abiraterone, ADT and SBRT...just to name a few... does SBRT with SOC have the ability to cure in OM PCa?? My MO said he believes so and so do many other MO's I believe... at least a long remission.... Cheers to a long remission/cure...

Fish

[Break60 in reply to cesces]

I know there’s no law against doing both and in fact I believe it’s necessary in order to keep the micromets from growing into visible mets amenable to SBRT. That’s what I’ve been doing. Just hoping against hope that it continues to work. Trying to stave off ADT by using SBRT alone may work for some but hasn’t worked for me with Gleason 4+5=9 Pca. BTW, I tested negative for BRCA 1 and 2 genes awhile back which was some consolation given I have sons and grandsons. I must say that I’m glad my mets have been few (oligomets).

Bob

[NPfisherman in reply to Break60]

We are all a clinical trial unto ourselves... ADT is a man killer and being off it feels so good... normalcy....I would look at trials and see if you can find one using SBRT plus Xofigo for micromets and short term ADT or ADT plus (abiraterone and/or apalutamide)... I totally understand your feelings about ADT... it sucks !!!

Fish

[Break60 in reply to NPfisherman]

Fish

I know we’re Gineau pigs. Using estradiol has been an outside the norm form of ADT. Have you used Xofigo or aby or apy?

Bob

[NPfisherman in reply to Break60]

Bob,

I used apalutamide for one month with a 1 month Lupron shot in a clinical trial using it before surgery... I tolerated it very well.... better than abiraterone which was what I was put on after my axumin scan showing one met with Lupron... I had SBRT 6 weeks later ... I liked the apalutamide better... Never used Xofigo, but if I have a BCR, it is early on my options for my next plan...

Fish

[cesces in reply to Break60]

I think it would be interesting to do a long term clinical trial with just three arms:

1. Adt

2. Sbrt

3. Adt + sbrt

And track more types of outcomes than just survival.

Maybe for some class of patients, the sbrt whack a mole approach may make sense.

[NPfisherman in reply to cesces]

I would like to do the following trial for oligometastatic patients post RP with PSMA scan prior to trial to insure treatment of all mets:

1) ADT plus abiraterone plus SBRT for 18 months

2) ADT plus apalutamide plus SBRT for 18 months

3) ADT plus apalutamide and abiraterone plus SBRT plus Xofigo for 18 months

The trial would include genetic testing and cfDNA testing initially and at 18 months and then annually, and look at BCR rate defined as a PSA greater than or equal to .2 or metastatic progression, and a 3D MRI scans would be done annually if PSA is "undetectable" . Study for 5 years with a 10 year f/u...

Fish

[cesces in reply to NPfisherman]

Unfortunately, there is no economic incentive for a pharma or university to fund it.....

Though perhaps there is a potentially patentable treatment in there somewhere.

[NPfisherman in reply to cesces]

That is why the PCF is so important.... They help fund trials like ORIOLE and RAVENS and there is NIH and the DOD that help out in finding the best treatment paradigm through funding... answers are coming...

[6357axbz]

Thanks for this post Don. It’s of great interest as a fellow oligo, especially one having undergone MDT with SBRT to all PSMA scan identified mets.

[NPfisherman in reply to 6357axbz]

You're welcome...Not sure if you did genetic testing, but a clear benefit has been shown in multiple Phase 2 trials for SBRT in oligos...Will we see cures in RAVENS or the City of Hope trial?? I think so...

Fish

[6357axbz in reply to NPfisherman]

I had genetic testing done. No abnormalities found. Why do you ask?

[NPfisherman in reply to 6357axbz]

You should take a good look at the ORIOLE trial then because those with no major mutations that received SBRT did best....100% over 2 years with progression free survival...please note that they were NOT on ADT in ORIOLE... I am watching to see if there is progression by year 3 or not... That's a fine remission/ possible cure.... The trial for us to watch is the one with ADT + AA/P + SBRT....

Fish

[6357axbz in reply to NPfisherman]

Is there such a trial, i.e., one with ADT + AA/P + SBRT?

[NPfisherman in reply to 6357axbz]

There is CORE which is SOC (defined by MO) plus SBRT and there is the one I listed which is apalutamide plus abiraterone plus SBRT and there is PEACE1 which is docetaxel with or wo abiaraterone and SBRT as well as ARTO which is for MCRPC and is abiraterone w/wo SBRT. I can not find any others currently.

Fish

[6357axbz in reply to NPfisherman]

Thanks Fish

[NPfisherman in reply to 6357axbz]

You're welcome.... from the STOMP study--MDT was associated with an ADT-free survival benefit regardless of the PSA doubling time (≤3 vs >3 months) or location of metastases (nodal vs non-nodal). I think that bodes well for us...

All the best...

Fish

[Break60]

I’ve had SBRT to bone oligomets twice after failed intermittent ADT. My problem is if I don’t stay on ADT I had fast doubling time Between treatments. So I switched to estradiol patches in Feb 2019 and had been undetectable for two years with way fewer side effects but last psa in Feb 21 was .2 so I may be back on the oligomets tx trail including second level ADT. I’m not sure it makes sense to do SBRT to each new bone met which shows up on psma scans. But I sure would like to avoid any form of ADT because it’s a man killer. Anything which lowers testosterone is a man killer! It’s such an unnatural state for a man. Do any of these doctors think SBRT without ADT is an acceptable way to treat guys with oligomets ?

[NPfisherman in reply to Break60]

I believe the RAVENS trial might be a consideration for you at Johns Hopkins with SABR plus Ra 223 (Xofigo) for micromets--see below:

clinicaltrials.gov/ct2/show...

I think the problem is that SABR alone is not enough and IADT may not be enough... my MO said he would treat me like a BCR patient and give me 2 years of ADT plus Zytiga and an RO gave me SBRT 6 weeks after I started my regimen... several guys on these forums followed a similar plan with solid success... Schwah threw in docetaxel first... he is heading into year 3 of a vacation I believe...

If I fail, then I will try SBRT with Xofigo and estrogen patches with Zytiga....Lupron brain fog is horrible... If you do SBRT again, then consider Xofigo for micromets, and that may help...

Best of luck on your journey...

Fish

[marnieg46]

Dave, following on from you post and in light of the subsequent discussions around Oligometastaic patients, I wonder if this recent video from UroToday added anything to the discussion?

urotoday.com/video-lectures...

[NPfisherman in reply to marnieg46]

Marnie,

Indeed, it does... The Take Home message is that more and more researchers, MO's, and RO's can see that SABR is safe and effective treatment for oligometastatic patients. Some posters are in denial believing there is no value to SABR despite multiple Phase 2 trials showing otherwise, as well as proof under the microscope of increased immune activity and T cell clones that will fight PCa. Those posters will be proven wrong and people that listen to them will pay the penalty if they are oligometastatic. It should be used with systemic treatment and not alone for best efficacy.

Thanks for the video and your reply....

Dave

[marnieg46 in reply to NPfisherman]

My pleasure Dave. Always helpful to have your thoughts on these ongoing developments. Enjoy your evening...

[TheTopBanana]

This compilation seems to also encourage pembrolizumab for oligomet: acsjournals.onlinelibrary.w... to hear your thoughts on this!

[NPfisherman in reply to TheTopBanana]

This one didn't open for me....Is the address incomplete..???

[TheTopBanana in reply to NPfisherman]

Does this one work? acsjournals.onlinelibrary.w...

[NPfisherman in reply to TheTopBanana]

Yes, it did. Good article.

The point is that this has real benefit for patients in the oligometastatic state. Some posters have referred to this as "whack a mole" and there is no value, but this author states that there are those that may be genetically less inclined to progress, which makes this treatment even more valuable, and thus, potentially may offer a cure to some... Identifying some of those patients occurred in ORIOLE trial.

In my opinion, the naysayers who support that whack-a-mole nonsense philosophy and get patients to buy into it are doing damage to patients who do not get treated.

Thankfully, SABR is becoming more SOC despite foolish naysayers....

Fish

[TheTopBanana]

Also interesting, to define it at a molecular level: practiceupdate.com/C/115908...

[NPfisherman in reply to TheTopBanana]

Exactly right... This is what I mean when I say some posters will tell you there is no hope/benefit using SBRT or MDT... 22% with bNED at 16 months....It will be good to see the 2 and 3 year f/u... Being off SOC treatment gives the body time to recover from no hormones, the weight gain, etc...

It is about adding time and QOL....

Like I said, posters that say there is no benefit to SABR are just misleading oligometastatic patients and the poor people that listen are paying the price. Sadly, those individuals don't care that they are damaging others because the facts don't fit their narrative...

Thanks for the reply and the article....

Fish

[NPfisherman in reply to TheTopBanana]

Interestingly, I have seen this article in other places, but there is little commentary.... Possibly, out of fear of the whack a mole crowd... How sad is that??

Fish

[Boywonder56]

I may be not reading correctly...but i had mets to l4, l5, anterior ramus....my hystoligy was ductal cribiform g9 .....they say no way to rpt...but i notice you had rpt....why and how did you get it done....b.w.

[NPfisherman in reply to Boywonder56]

If by rpt, you mean Robotic Prostatectomy, I was negative on bone scans and CT, so an RP was indicated based on no mets, but as we know now, these imaging types are not best for PCa. When I had a BCR of 2.92 in 6 months, I had an Axumin scan which found a lytic lesion that I received treatment for after starting ADT plus Zytiga.

If by rpt, you mean radiation as in SABR, I was not Ductal, but had adenocarcinoma (most common) which made me a candidate for SABR. Ductal is very aggressive and so if they would not do SABR then it may have been because of the Ductal. Getting it done did mean an appeal for a denial from the insurance company, but I saw Dr. Burton at UPMC who has done some of the Phase 2 trials for SABR with Dr. Herron.

Fish

[Boywonder56 in reply to NPfisherman]

Was the former...thanks for responding

[Boywonder56 in reply to NPfisherman]

Based on what you know now would you have had the robotic. And do you believe it's best to leave and aggressive Beast intact

[NPfisherman in reply to Boywonder56]

I agree with Nalakrats in the concept of "Take out the Mothership", because it evolves with communication with metastases through mRNA... I believe in hitting it hard early...I took out te mothership and the second mothership.... I believe that "if no one wants to do the RP", THEN a great alternative is cryotherapy with pembrolizumab and sangrostim x 30 days as I recall was the regimen used recently and it was very successful in preventing a relapse. I will see if I can find it...the problem with leaving things intact and communicating is evolution occurs and in cancer, it means more aggressive. One could do a tumor biopsy with the cryo regimen following, and then get the APCEDEN vaccines for a year...

Fish

[NPfisherman in reply to Boywonder56]

I have a good memory.....see article with specific attention towards the bottom when they go into PCa results....

abstractsonline.com/pp8/#!/...

Fish

[NPfisherman in reply to NPfisherman]

From the article:

Among the 19 evaluable PCa patients, there were 9 (47%) CRs and no PRs, for an ORR of 47%. 5 (26%) patients showed SD, and 5 (26%) progressed. 13/21 (62%) of patients had post-therapy PSA reductions of >50%.

12 PCa patients were ADT-naïve (11 evaluable by RECIST) and there were 9 with mCRPC (8 evaluable by RECIST), and positive responses were seen in both groups, with ORRs of 55% and 38%, respectively, and PSA reductions of > 50% in 75% and 44% of patients, respectively.

These antitumor responses have been durable in many patients, with CRs to date ranging from 1 to over 4.5 years post-treatment. Encouragingly, this durability of response was observed both in ADT-naïve patients and in those with mCRPC.

Fish

[Boywonder56 in reply to NPfisherman]

Thank you fish....

[NPfisherman in reply to Boywonder56]

See my series of responses...