Lu-177-PSMA-617 seems to beat Jevtana in a randomized clinical trial. In those countries where it is already available, it is the preferred third-line therapy based on reduction of PSA and toxicity.
Everything is confusing to me when it comes to this disease although I came from a science background. Anyhow, these are great questions. Thanks for posting them.
Thank you TA for posting this! We are in the process of getting an FDG scan this wk because we are seriously considering doing Lu177 come July 1. My husband’s last 18F-PSMA Pet/CT was 2wks ago. I hope the time gap between the 2scans is still ok.
Another question i would like to raise is, in the event Lu177 does not work, can one do docetaxel or should cabazitaxel be used instead?
You had posted 10 months ago regarding Lu177. This article might be useful to you - wchh.onlinelibrary.wiley.co...
PSMA (prostate-specific membrane antigen) -targeted radiopharmaceutical therapy could be more effective and better tolerated than current chemotherapy in patients with metastatic castration-resistant prostate cancer (mCRPC), according to a recent trial.
The Australian study published in the Lancet, compared Lutetium-177 [177Lu]Lu-PSMA-617 (intravenously every six weeks for up to six cycles) with cabazitaxel (20 mg/m2 intravenously every three weeks for up to ten cycles) in 183 men with mCRPC.
PSA responses were more frequent among men in the [177Lu]Lu-PSMA-617 group than in the cabazitaxel group (65 vs 37 PSA responses; 66% vs 37% by intention to treat; difference 29% (95% CI 16–42; p<0·0001; and 66% vs 44% by treatment received; difference 23% [9–37]; p=0·0016). More serious adverse events occurred in 33% of men in the [177Lu]Lu-PSMA-617 group versus 53% of men in the cabazitaxel group.
The treatment of patients with mCRPC has mostly involved androgen receptor-targeted therapies and cytotoxic chemotherapy for over a decade. [177Lu]Lu-PSMA-617 is a radiolabelled small molecule that delivers β radiation to cells expressing PSMA and thus offers a new approach to treatment.
A commentary in the same issue of the journal notes that completion of the study is a considerable accomplishment, given the absence of a pharmaceutical industry sponsor. It is rare for a trial to be done in which the synthesis of the drug is done by the participating academic institutions and the funding largely provided by charities including Movember, it says.
No problem with 2 week time lag. If he was successful with docetaxel before, he can try it again to save money.
I like that this trial compared two treatments which will likely be the choice for many after Enzalutamide or Abiraterone.
Two things to point out. The trial participants were "cherry-picked" for how PSMA avid they were. I understand why they did that and it makes sense, but it does skew the results. Those of us making this choice will be looking at our own situation before choosing this or chemotherapy.
The second issue is that we only see the PSA response, not the progression-free survival or the overall survival yet. I would expect chemotherapy to not have as good of a PSA response because it's not selectively going after the PSA producing cancer cells. So we still need to see how LU-177 compares with PFS and OS.
Overall, it's great news since it gives us another option.
I don't think the results are "skewed," they are rational patient-selection criteria that should be used by any heavily-pretreated man interested in Lu-177-PSMA therapy. Those criteria can spare men a useless or damaging therapy and its side effects.
I agree that OS is very important. There is no point to undertaking any therapy unless it is palliative or increases survival. However, I don't understand your point about going after the PSA-producing cells selectively. Both Lu-177-PSMA-617 and Jevtana kill adenocarcinoma prostate cancer cells that put out little PSA or a lot of PSA. Jevtana additionally kills cells that do not express PSMA.
This represents the best case senario for LU-177 and that's good to know.
What I meant by skewed is we are comparing two treatments and one of the two has a selection bias while the other does not. If for example, we did a comparison between Olaparib and Cabazitaxel, but only let those with BRCA2 mutations participate, we would get a biased result.
So all of those patients that didn't get treatment at all in this trial, still need to be counted.
There are some problems with the selection bias argument.
The first is that it's unethical to treat patients that we already know, because they are not PSMA avid, won't benefit from the treatment. They'll suffer the side effects and they'll be prevented from taking other treatments while the trial is in progress while getting little or no benefit.
A second is that men whom we know are likely to benefit will see reduced benefit numbers from the trial if men are included whom we know will not benefit. A man who could reasonably hope for X months of extra life may only see 1/2 X in the trial results. That can be partially overcome by reporting different cohorts of patients separately, but see below.
A third, and not inconsiderable problem, is that the cost of the trial will increase if men who are not expected to benefit are included. Alternatively, in a fixed price trail (very common I think) if the trial investigators have, say, 2 million dollars in grants and it costs $10,000 for each patient (made up numbers here), it would be more valuable and more statistically significant to treat and process results from 200 patients who might benefit than from, say, 100 who are already known not to benefit and 100 who are hoped will benefit. The money will buy more information and more precise information that way.
I do agree that seeing overall survival numbers is very useful. However I'd rather the investigators publish the PSA numbers as soon as they're available than have them wait until meaningful overall survival numbers are available. Hopefully, they'll follow up with a second report when OS numbers are meaningful, and maybe a third report too.
That is not what is meant by the term "selection bias." Selection bias is eliminated in randomized trial, which is why they are randomized. They are as unbiased as they come. Selection bias is why most observational studies are flawed - those that get a treatment are different from those who get some other treatment. Setting patient criteria for everyone assures that there is no selection bias.
That's a problem with LU-177 / PSMA.. There are always cancer cells that don't express any PSMA and they are not effected by the treatment..Combining Lu-177 with Jevtana sounds like a good idea..But now we come to the who is going to pay for it part..
That's right, some cancer cells don't express PSMA. For example, neuroendocrine PCA leads to PSMA suppression. Here's an article for anyone interested. pubmed.ncbi.nlm.nih.gov/304...
In a recent small randomized trial (phase 2a) the combination of docetaxel and Ra-223 was well-tolerated and performed better on several biomarkers compared to docetaxel alone, so it isn't unreasonable to think that Lu-177-PSMA may be synergistic with Jevtana (perhaps with Provenge too).
As long as your body and your wallet can absorb it, multiple treatments simultaneously administered can work very well but the patient must be closely monitored to address possible side-effect problems..Just getting your doctors to go along with it can be difficult..
Thanks for the info Tall_Allen. It will come in handy when I am crossing that bridge, which I hope I wouldn't be doing so soon.
However, a point to note, over in Singapore, our oncologists, at least those in the government hospitals, tend to do things a little different, if I am not mistaken.
This is a useful post, thank you. I'm hoping to start Ra-223 treatment soon, and further ahead would prefer Lu-177-PSMA-617 to Jevtana but at present Lu-177-PSMA-617 is not approved here in Japan.
Thanks, yes, good idea but Provenge is not available in Japan. Doctors do know about it. I have family in Wake Forest, NC, and could visit for treatment sometime but trips to the USA not likely for the foreseeable future. Best wishes.
10 months ago you had posted about Lu177. This may be of interest to you. Hopefully now it is available somewhere in Japan for you.
wchh.onlinelibrary.wiley.co...
PSMA (prostate-specific membrane antigen) -targeted radiopharmaceutical therapy could be more effective and better tolerated than current chemotherapy in patients with metastatic castration-resistant prostate cancer (mCRPC), according to a recent trial.
The Australian study published in the Lancet, compared Lutetium-177 [177Lu]Lu-PSMA-617 (intravenously every six weeks for up to six cycles) with cabazitaxel (20 mg/m2 intravenously every three weeks for up to ten cycles) in 183 men with mCRPC.
PSA responses were more frequent among men in the [177Lu]Lu-PSMA-617 group than in the cabazitaxel group (65 vs 37 PSA responses; 66% vs 37% by intention to treat; difference 29% (95% CI 16–42; p<0·0001; and 66% vs 44% by treatment received; difference 23% [9–37]; p=0·0016). More serious adverse events occurred in 33% of men in the [177Lu]Lu-PSMA-617 group versus 53% of men in the cabazitaxel group.
The treatment of patients with mCRPC has mostly involved androgen receptor-targeted therapies and cytotoxic chemotherapy for over a decade. [177Lu]Lu-PSMA-617 is a radiolabelled small molecule that delivers β radiation to cells expressing PSMA and thus offers a new approach to treatment.
A commentary in the same issue of the journal notes that completion of the study is a considerable accomplishment, given the absence of a pharmaceutical industry sponsor. It is rare for a trial to be done in which the synthesis of the drug is done by the participating academic institutions and the funding largely provided by charities including Movember, it says.
You sure know how to ask questions, all worth an answer, maybe I can't answer all because every man finds that he will get a different sort of treatment.
For men where there is high avidity for Ga68 in the PsMa scan before Lu177, then Lu177 might be better than any chemo. I had Lu177 right after Chemo failed. My supervising doctor in LU177 clinic for No3 shot of Lu177 was a Pca research doc filling in time between research grants from Govt. She said that although chemo failed, it made my Pca express more PsMa and this attracted more Lu177 thus it more effective, so less shots were needed. But that was a bit late, after 3rd shot, but by final 4th shot, I had been on Xtandi for 7 weeks and reduction of Psa after 4th Lu177 shot was good.
Peter Mac in Melbourne is exploring all sorts of things to do with Lu177, also at St Vincents in Sydney.
But I got a nice extra year year of life with Lu177 which was free of the threat of some other darn treatment that hardly ever works. Without Lu177, I might now be in palliative care.
Psa was 0.32 last November, down from 25 a year before. But now its 10, so action must be taken and I have booked another PsMa scan and Lord Noze what that may or may not reveal, and some of the things in your your list might be tried. Just how well our so called experts know about all these things is not known, so I am bit at their mercy. Ac225 works better than Lu177 for bone mets and probably ALL mets, but its pretty strong stuff and permanent side effect of dry mouth is more likely. So docs have told me they might consider more Lu177 if next PsMa scan showed I'd do good with it again but maybe with with a small amount of Ac225 added. I am presently so darn healthy I'd handle a couple more doses of Lu177 at least.
The dose level for Lu177 is worked out before having each dose, based on what the docs see in scans. If Psa is low, and mets are not large, uptake of Lu177 won't be very high, and using bigger dose won't make uptake much higher. 1/2 the dose is expelled by body in first 24 hours, and its pointless to expose the healthy parts of body to a dose that's too high. Bone mets take time to kill, and its a case of a little bit at a time, and after some initial Pca killings, bone mets change in structure and blood supply so next shot of Lu77 can get in to kill more hard bone in mets again. Its a bit like bringing down a Medieval Castle where you have to burrow under the castle to weaken its foundations, causing a wall to collapse, bit by bit.
I have been told about FDG scans may follow next PsMa scan if needed. I cannot know yet if my Pca could be reduced as much as it was last year by Lu177. All other things are maybe not as good but at this point, I just cannot know yet.
Radium 223 has reputation of making bones brittle, because it is not targeted with a ligand chemical and it just goes where calcium disturbances are happening, which may be where arthritis is happening. Ra223 is so seldom used here I don't know who I'd talk to to find out about it. Its usually used where there are no soft tissue mets and all mets are in bones.
I know you're not going to believe this (cause I don't) but when I played football (US not soccer) for a Greek team while attending an "Egyptian University" we used to punt the ball with two feet (not one),,,, One foot for distance the other for accuracy. I bet that's why you broke your ankle cause you only used one foot for the punt.
p.s. I had a hard time picking a position on the team....NO one wants to play center or tight end on a Greek football team... Mend well....
Thanks for post too; look forward to Peter Mac's (Hofman's Group) OS results.
To briefly answer your "Many open questions":
• Should it be used soon after second-line hormonals?
Yes. Indeed in the future I think it will be used as a mop-up after primary treatment (RP or IMRT)
• Should it be used before or soon after docetaxel?
Before, it has higher efficacy with less side effects for me at least. ( 5cycles of Lu versus 6 cycles of docetaxel)
• Would the problem of heterogeneity be minimized if Jevtana and Lu-177-PSMA were given simultaneously?
It may be minimised but the patient may also be! Too toxic in the opinion of one group carrying out this therapy (I asked for it).
• Should it be used in minimally metastatic patients?
Yes, see above.
• Should it be used in newly diagnosed metastatic patients?
Yes.
• Should it be used with immunotherapies (e.g., Provenge, Checkpoint inhibitors)?
• Will PARP inhibitors enhance the cell-kill rate?
There is evidence that Olaparib radiosensitizes PC mets for Lu; a study is under way at Peter Mac at this moment to assess this.
• Is PSA the best biomarker of effectiveness?
Surely imaging is more accurate, but PSA does parallel lesion progression fairly well.
• What are the best radionuclides to use (e.g., Ac-225, Th-227)? At the moment Lu, because of its history of use and B penetration distance. But Ac for those with compromised bone marrow but there is potential irreversible knock out of salivary glands and possible kidney damage so it may be limited to late stage mPC patients, as least currently.
• What are the best/most specific ligands to use? (e.g., PSMA-617, PSMA-I&T)
. They are virtually identical in efficacy
• Are there better surface proteins to target, perhaps simultaneously (e.g., FAPI)
• How do they compare to PSMA BiTE therapies?
• How does it compare to Xofigo for bone metastases? I have not heard of anybody doing a comparison; it is needed
Hi Rob. You're probably aware of this but just in case you're not...
Urotoday has many videos available that you can stream with current updates on the various developments and research projects. Michael Hofman's work has featured quite a bit in the ones I've viewed in April and May. These come at no cost and also with a script of the interview are only about 15 or 20 minutes so easy to watch and always informative.
Actually, one I question is whether your oncologist is right that Lu-177-PSMA cannot be combined with chemo. A recent small trial showed no increase in hematological toxicity from combining Xofigo and docetaxel (in fact, febrile neutropenia was lower when the reduced dose docetaxel was used in the combination). And the combination reduced biomarkers for a longer time than docetaxel alone. Is it different for Lu-177-PSMA? Certainly worth an RCT. You may want to forward this to your oncologist and discuss further:
Good suggestion. Perhaps allowing a minimal time distance between treatments as I am doing currently (ie Lu now, after Docetaxel 2 mo ago) is achieving something similar.
So...a lot more questions than answers. I'm not there yet, still on Zytiga(generic), but looking to future treatments. Thanks for posting this Tall Allen
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