First Follow-Up on Lu-J591 treatment following SBRT

[MateoBeach]

I previously described my treatment plans for my oligometastatic (<4 sites, in my case 2 lymph nodes in pelvis and abdomen) With a two-stage approach:

I explain this in somewhat more detail in my post "Why I Choose an Unproven Treatment". Many have asked me to post an update on the treatments, so here goes.

Antes de Nada (before anything), I wish to express my deep gratitude and joy in meeting with other HU-APC families while I was in Australia. Especially to Marnie and husband Ron and their whole delightful family that took such amazing and generous care of me during the week I spent in Sydney

First, I had "spot" targeting of the two new nodes identified on PSMA scan. This was 5 treatments in 5 days with external beam radiation, SBRT.

See below for some very new information on the effectiveness of metastasis targeted therapy that just is coming out for ASCO2022.

Then four weeks later (this month) I went to Perth, Australia for an experimental form of Lu177-PSMA treatments with a monoclonal antibody radioligand called J591. This is not the same as the Pluvicto treatments which use Lu-PSMA-617. The intention is to attempt targeting of all unseen micro-metastases and circulation cancer cells. It is an unproven regimen, though a clinical trial is underway.

The last of the two treatment infusions was just this last Friday. It is still at work inside my body, as evidenced by how I set of radiation detectors in the San Francisco airport and was detained for an hour despite providing documentation. Note that the level of radiation is below and danger level to others, less than 10 micro-Sieverts per hour at one meter. Probably more radiation from flying at 30,000ft+ for 20 hours.

I will not have any indication of actual effectiveness until follow up PSAs and PSA trends in the coming months. For now the molecular targeting radiation is "still at work".

So this is an early report on the experience. It is a very long way to Perth from Oregon! San Francisco to Sydney was 14 hours. Then 5 more hours flying across the continent to Perth. (No direct flights from the West Coast to Perth.) Perth was lovely and genteel. Great long walks along the Swan River and the enormous King's Park and Botanical Gardens. Wonderful, if expensive, restaurants crowded with friendly raucous Aussies.

GenesisCare (Theranostics AU) is in a nice suburb in a brand new building adjacent to St John of God Hospital, with state of the art equipment and amenities. Dr. Nat Lenzo and staff to careful attentive care of me and made sure I was comfortable. The isotopes arrived right on time. And IV infusion was easy-peasy. 15 min to go in then a saline drip for two hours before they released me by Uber back to my very comfortable hotel. No quarantine required, just some sensible precautions regarding prolonged closeness.

Basically, I had just two side effects. mild to moderate fatigued started on the second day and lasted until the 11th day after infusions. I could still do my long daily walks but needed an afternoon nap and did not feel like doing intense exercise in the hotel gym before it cleared. The other SE was some diarrhea. Lu-J591 is cleared by the liver and into the intestines via the bile. Messy and inconvenient but not severe. This too resolved by day 11. So it is, in all, a very easy treatment to tolerate.

Bone marrow suppression is the major risk. For anemia that some require transfusions, for low platelets that can also require transfusions, and low WBC counts. I had blood tests done before the 2nd infusion and my levels were all fine. virtually identical to my pre-treatment tests. Nat said that if it was going to be severe he would have seen a drop by that time as an indication. So all good.

"Metastasis-directed therapy" (MDT: either SBRT or surgical excision) in oligometastatic PC often fails in the long run. Over 60% of patients, even if the treated sites are completely resolved, will have recurrence nearby or distant within two years. (So that is why we added on this second form of treatment.) Many call this playing "whack-a-mole" and doubt the utility of it.

A study that was published as an abstract for ASCO 2022 today, argues otherwise. That it is beneficial for many, even without a second systemic therapy. This is true overall. And there is especially benefit for those with high-risk mutations (ATM, BRCA1/2, Rb1, or TP53).

Before someone replies by saying, "Oh that just shows improved progression-free survival (rPFS or cPFS), but does not prove improved overall survival (OS)." I will refer them to another ASCO 2022 abstract today that shows that PFS is indeed a valid surrogate intermediate marker for Overall Survival! That link follows at the bottom of this post.

meetings.asco.org/abstracts...

Long-term outcomes and genetic predictors of response to metastasis-directed therapy versus observation in oligometastatic castration-sensitive prostate cancer: A pooled analysis of the STOMP and ORIOLE trials.

Background:

Prospective reports suggest metastasis directed therapy (MDT) in oligometastatic castration sensitive prostate cancer (omCSPC) is associated with improved treatment outcomes. Here we present long term outcomes of the phase II STOMP and ORIOLE trials and assess the ability of a high-risk (HiRi) mutational signature to provide prognostic and predictive information regarding MDT response.

Methods:

Patients with omCSPC (< 3 lesions) enrolled on STOMP (n = 62) and ORIOLE (n = 54) randomized to MDT or observation were pooled. The primary endpoint was progression-free survival (PFS) defined as either PSA or radiographic progression, initiation of androgen deprivation, or death. Secondary endpoint was radiographic PFS (rPFS) defined as radiographic progression or death. Both were calculated using the Kaplan-Meier method and stratified by treatment group. Next generation sequencing (NGS) was performed to identify a HiRi mutational signature defined as pathogenic mutations within ATM, BRCA1/2, Rb1, or TP53. Cox proportional hazards regressions were fit to calculate hazard ratios (HR) and assess the prognostic and predictive values of HiRi mutational status.

Results:

Median follow-up was 52.5 months. Median PFS was prolonged with MDT (11.9 months) compared to observation (5.9 months) with a pooled HR of 0.44 (95% CI, 0.29 – 0.66, p-value < 0.001). MDT was associated with PSA decrease in a majority of patients (84%) as compared to the observation group (41%). On NGS, the incidence of a pathogenic mutation in a HiRi gene was 24.3%. HiRi mutation was prognostic for PFS -- in those without a HiRi mutation median PFS was 11.9 months compared to 5.9 months in those with a HiRi mutation (HR of 1.74, p = 0.06). HiRi mutation was also prognostic for rPFS -- those without a high-risk mutation experienced median rPFS of 22.6 months compared to 10.0 months in those with a high-risk mutation (HR 2.62, p < 0.01). Tumors without a HiRi mutation treated with MDT experienced the longest PFS (13.4 months) while those with a HiRi randomized to observation experienced the shortest PFS (2.8 months). Stratifying by both treatment arms and HiRi status appeared to show a differential benefit to MDT, with those with HiRi mutations experiencing a larger relative magnitude of benefit to treatment: (HiRi mutation: HR of 0.05, p < 0.01; no HiRi mutation: HR of 0.42, p = 0.01; p interaction, 0.12) suggesting a HiRi mutational status can provide information regarding differential response to treatment.

Conclusions:

Long-term outcomes from the only two randomized trials in omCSPC suggest a sustained benefit to MDT over observation. A HiRi mutational signature appears prognostic for outcomes in omCSPC and those with HiRi might have a relatively larger magnitude of response to MDT. Future studies are needed to optimize patient selection. Clinical trial information: NCT02680587.

The second abstract mentioned follows: (As above, so below!)

meetings.asco.org/abstracts...

Assessing intermediate clinical endpoints (ICE) as potential surrogates for overall survival (OS) in men with metastatic hormone-sensitive prostate cancer (mHSPC).

Background:

We hypothesized that radiographic progression free survival (rPFS) and clinical PFS (cPFS) are valid surrogates for OS in men with mHSPC and could potentially be used to expedite phase 3 clinical trials. This hypothesis was investigated by the STOPCAP M1 Collaboration.

Methods:

We obtained individual patient data (IPD) from 13/26 eligible randomized trials comparing treatment regimens (androgen deprivation therapy (ADT) or ADT + docetaxel in the control or research arms) in mHSPC. We evaluated the surrogacy of rPFS and cPFS as potential ICEs. rPFS was defined as time from randomization to radiographic progression (defined per protocol) or death from any cause whichever occurred first; cPFS was defined as time from randomization to date of radiographic progression, symptoms, initiation of new treatment, or death, whichever occurred first. OS was defined as time from randomization to death from any cause, if patients had not died they were censored at the date of last follow-up. We implemented a two-stage meta-analytic validation model where conditions of trial level and patient level surrogacy had to be met. We computed the surrogate threshold effect (STE), which is the minimum ICE treatment effect necessary to estimate a non-zero effect on OS.

Results:

IPD from 8592 patients randomized from 1994-2012 from 13 trials were pooled for a stratified analysis. There were 5377 deaths, of which 3971 (74%) were due to prostate cancer. The median follow-up for surviving patients was 75.6 months. In addition, there were 6227 rPFS and 6314 cPFS events. The median OS, rPFS and cPFS were 49.4, 26.8 and 25.2 months, respectively. The STE was 0.82 for rPFS and 0.84 for cPFS.

Conclusions:

Both rPFS and cPFS appear to be valid surrogate endpoints for OS. A surrogate threshold effect of 0.82 or higher makes it viable for either rPFS or cPFS to be used as the primary endpoint as a surrogate for OS in phase 3 mHSPC trials and would expedite trial conduct. Validation of these ICEs in trials with drugs having other mechanisms of action is planned. Clinical trial information: Several.

[Tall_Allen]

Radiological PFS (progression on imaging) and clinical PFS (symptomatic progression) are good surrogates, but biochemical PFS is not. Oriole had very short-term follow-up so almost all of the "PFS" they reported was biochemical PFS. MDT treats PSA, so one cannot use bPFS as an endpoint.

[Schwah in reply to Tall_Allen]

Hi TA. Let me speak for a number of men here that are confused and frustrated. We are the ones that generally just go to the conclusions on these studies as a lot of the info that comes before is hard to follow. The conclusions coming from well respected researchers tell us that MDT works. Then we hear from you, who most of us have come greatly to respect and you come to the conclusion that they are wrong. So we are left floundering for the truth.

We ask ourselves, (and by this post we ask you) why would these professionals running these trials come to conclusions about the efficacy of MDT that you basically dismiss as nonsense? Please help us understand. Are these researchers A.) intentionally misrepresenting the data B.) unintentionally just coming to the wrong conclusion? C. None of the above. Please try and help us make sense of it all. Thanks as always for your time TA.

Schwah

[Tall_Allen in reply to Schwah]

Schwah- I don't know if it works or it doesn't. And if it does, to what extent. I'm pretty consistent in saying that there is not yet enough evidence to make that call. What I know is that ADT and other systemic therapy works. So, I always recommend hedging one's bet - always use systemic therapy and also add MDT in those places where it is safe to irradiate.

These "well-respected researchers" you mention - have they researched the subject? They are not "running these trials." I am well aware of all the trials on the subject, and many of the doctors who are most vocal about it do not have any RCTs runnings. In fact, they can't run RCTs. Let me explain.

To run a randomized clinical trial requires "equipoise" on the part of the investigator. Equipoise means that, based on how you feel now, you are indifferent to randomly assigning patients to one group or another, Otherwise, you would be doing something that you consider to be unethical.

So, I believe that the doctors you mention have "swallowed the Kool-Aid" and believe what they are saying. But their beliefs are not based on good science. I know a lot more doctors who are good scientists.

If you want to know the RCTs that are out there, there is a list of them at the end of this article:

prostatecancer.news/2020/07...

Anyone who claims to know before any of those RCTs are finished, is stating an opinion, not a fact.

[Schwah in reply to Tall_Allen]

Thx for the thorough response TA!

[Tall_Allen in reply to Schwah]

BTW- It's breast cancer, but this RCT showed that MDT to oligometastatic sites did not slow progression or extend survival:

meetings.asco.org/abstracts...

I think we can say with assurance that if there is value in oligo-MDT, it is not true for every cancer.

[keepinon in reply to Schwah]

That was a great question Schwah. Thanks for asking it. I was wondering the same.

[Spyder54 in reply to Schwah]

Steve, please remember that the Stampede Trial with 10,000 Advanced Prostate Cancer has about 2,000 Men in their Arm H. This is a Stage 3 Trial w Peer review that showed that Men on Lupron, Abiraterone/Zytiga-pred, who had SBRT/SABR to their primary prostate gland only had an 81% 3yr (so far-ongoing) OS. This is one of the best OS numbers of any Arms in the Trial. Best, Mike

[MateoBeach in reply to Tall_Allen]

Well, MDT treats metastatic lesions of sufficient volume and activity to be identified on scans. So it decreases tumor burden in oligometastatic disease. Therefore PSA can give some indication of the degree of reduction and the degree of remaining burden if it was not highly suppressed by ADT in the HSPC state. So I believe it is still a useful marker until longer term follow up scans (and symptoms) provide stronger evidence. For example in my case, mHSPC and not on ADT, I can use it to guide my ongoing use of cyclic SPT along with periodic scans.Hopefully, more mature data with longer term follow up will clarify if bPFS will ultimately be useful or not.

[Tall_Allen in reply to MateoBeach]

The danger is treating PSA and not treating the cancer:

prostatecancer.news/2020/07...

[MateoBeach in reply to Tall_Allen]

Yes I have read and considered that and heard you mention it several times. But still think in treating the cancer it is a useful marker as long as the cancer is still producing it and correlates with scans. As are PSA kinetics in some clinical situations. I suspect that many may be confused by the statement. Certainly those who are obsessed with PSA levels and tiny changes can benefit from considering that. So thanks for highlighting it for all.

[Spyder54]

Thank you Paul for sharing your J591 experience thus far. It is bold to go where few have gone before you. Clearly you have used your intelligence and intuition in an effort to have an extended remission. Man, we are all pulling for you to have good scans and undetectable PSA for years. The SBRT should take care of the few Mets and the J591 should work on the micro Mets. I’m searching for your term for wiping the landscape clean, and brain fog won’t let me find it. Something like total Anihilation ?Keep us posted. Thanks, Mike

[MateoBeach in reply to Spyder54]

Thanks Mike. “Extinction Vortex” is the theory I referenced previously in regards to evolutionary dynamics in treatment. But “Annihilation” woks fine.

[Spyder54 in reply to MateoBeach]

@Mateo. Right on ! Brain fog holds me back from time to time. Hope we all find “Extinction Vortex thru some available combination. Mike

[Brysonal]

Wishing you all the best with this pioneering approach. My view is that we know so little about what could work and we all agree there is nothing fun about hormone therapy so really need a better solution and I see the term ‘unmet need’ over and over in clinical trial info. Fingers crossed we live to see that change.

When my dad was diagnosed in 2010 already advanced he followed standard of care so hormone therapy only until he went castrate resistant 5 years later with late chemo extending his life to June 2016. It seems like yesterday. He missed my sons wedding, me becoming MD and lots of family time. I still talk to him a lot.

We now know he fitted the profile for both early chemo and early radiation of the prostate which is standard of care today thanks to the pioneers taking part in STAMPEDE and similar clinical trials. If I had a timeturner I would learn more and have encouraged either clinical trials or pushing the boundaries beyond SOC. I was busy with my career and family and it’s my biggest regret.

[Spyder54 in reply to Brysonal]

@Brysonal. It’s all good Bro. We still hv time to figure this thing out. There is a giant chess match going on here where we are “the Pawns”. There is a combo that is available, or soon will be that gives us extended remission.Mike

[Purple-Bike]

Paul, thanks for letting us know about your pioneering treatment to target micromets and circulation cancer cells. Glad to hear that so far side effects are tolerable. Please keep us posted.

[Ramp7]

This is a great read. Positive energy being sent your way.

[slpdvmmd]

Thank you for your thoughtful post/update. I think we have to keep in mind that prostate cancer is a single name for many tumor types. My consistent observation during 40+ years of medical practice and research (and I would clarify I was not a cancer researcher) is that there is almost always a subset that responds. The medical industrial complex tends to disregard those responders and look for a global cure when in fact we all to often need an individualized treatment plan.

[MateoBeach in reply to slpdvmmd]

Wise viewpoint none of us are actually the median patient in a clinical trial. Unless N=1. Thank you.

[j-o-h-n]

If I would have known that Pca is so interesting, I would have had it earlier....

Good Luck, Good Health and Good Humor.

j-o-h-n Thursday 06/02/2022 7:17 PM DST

[TK934]

Hi! This is my first post, but I wanted to thank you for sharing your experience. My husband is also taking the path of Lu177/J591, and I believe your second treatment was the day he had his first. We are currently in Perth, awaiting the second treatment in two day’s time.

My husband might be a good example of the positive results possible with Lu177. He had his first Lu177 treatments for tumors in the lymph nodes in Nov ’17 and Jan ’18 with Dr. Nat Lenzo, with a remission lasting until a PSMA-PET scan in August ’20 showed a tumor in his prostate (but not in lymph or bone). In October ’21, the PSMA PET scan showed three small tumors in the lymph nodes and one on a rib. Since then, he has followed a treatment plan similar to yours – standard radiation treatment focusing on the tumors in December ‘21. A follow-up PSMA PET scan in March ’22 showed that while the treated tumors were reduced significantly, there were two new tumors in different areas. A more systemic approach was required, which is what led David to be sharing a treatment room with you in Perth, Australia, nearly two weeks ago.

We are hoping that the Lu177/J591 treatments will continue to buy David more time. We are grateful to have avoided ADT up until now, but we anticipate ADT will be in David’s future. We closely follow the developments in that treatment, and we are impressed by the recent developments. We are working with both a radiation oncologist and medical oncologist in Ottawa, and we are prepared to go down that road when it is necessary.

To complete the story a bit more -- David (now 68) was first diagnosed in Jan '13, G7, PSA 12. After active surveillance and a rise in the PSA, David underwent a IRE treatment in Germany for the prostate tumors in Nov '16. A follow-up PSMA PET scan in Sept'17 found the initial tumors in the lymph nodes, and our German doctors recommended Lu177 as a possibility. David has had no side effects from the first Lu177 treatment, but he has had fatigue from the radiation in Dec '21 and from the Lu177/J591.

Wishing you all the best.

[Spyder54 in reply to TK934]

Wow, TK934. I am following your progress for sure. You seem to be on the leading edge of so much going on in the APCa world. Nano Knife (IRE) just FDA appvd in US last year has a Phase 1 Trial going on at MSK for Interm PCa. I did not qualify, but flew to NY to meet w Dr Jonathon Coleman running the study. He told me what you hv learned. Great technology, but not perfect. Nothing seems perfect. He introduced me to Dr Sean McBride who said I was a candidate for Image Guided SBRT (MSK-Precise). My PSA went from .260 in Dec ‘21, to .095 in May, to .032 last week. The J-591 is hopefully a way to deal with the micro Mets in the blood stream (like liquid Radiation). I did NOT avoid ADT as your husband. I like what Mateo is doing with mBAT. It feels like we are making progress. I know, it all works, yet nothing is perfect. We are all in different orders of therapy. There may be a more perfect combo for the next guy. Just one big human experiment. A chess match. All trying to make their best move. With a life in the balance. Best to you and yours, Mike

[MateoBeach]

Thank you for reaching out to me TK934. I do remember you and chatted with your husband while receiving our infusions. Also I asked him if he participated in HU-APC forum. He said his wife “took care of that “, or something like that, when you were out of the room at that time.My only side effects are some mild fatigue and about 2 weeks of unpredictable (and inconvenience) from excretion of the Lu-J591.

My wife, Johane, and I are headed to BC Canada next week for a long delayed motorcycle and RV trip around Vancouver Island and Western BC.

I do not tolerate (hate) ADT also. For over a year now I have been on modified BAT, cyclic high dose Testosterone. Two months on then one month off. This has worked well for me so far. PSA remains very low <0.2, and body feels great. As with J591, it is not SOC. I had rather severe hypogonadism and sarcopenia that justified trying it. Took some convincing for my MO to agree.

Enjoyed my time in Perth and a side trip to Sydney. Especially long walks along the Swan River and in King’s Park via the many bikeways.

My regards to you both. Please keep in touch. Paul

[TK934 in reply to MateoBeach]

Enjoy British Columbia! My husband and I lived there for several years. When David retired, we moved to Ontario. We also are enjoying Perth -- enjoying many of the same walks and areas that you discovered. We will continue to monitor and stay in touch.

All the best, Hilde (TK934)