New PSMA (TTC-PSMA) directed therapy with alpha particles using Thorium 227
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Ottawa, ON, Canada (UroToday.com) Dr. Hartwig Hennekes opened the Symposium with a business perspective on future directions for targeted alpha therapy (TAT). Bayer currently has Xofigo, a drug using Radium-223(Cl2) approved in 54 countries for the treatment of patients with castration-resistant prostate cancer, symptomatic bone metastases and no known visceral metastatic disease.
Bayer is looking to expand to treat other types of cancer that would require a more conventional path of labelling an isotope to a chelating agent which would be linked to an antibody expressed by the tumor of interest. Radium-223 is difficult to chelate. Thorium (Th227) looks like an attractive alternative since it could be supplied by the same production facility that supplied the Radium-223. The thorium labelled chelate (targeted thorium conjugate, TTC) is now in pre-clinical studies when linked to the HER2 antibody appropriate for a number of tumors including breast cancer. Phase I trials are ongoing with TTC-PMSA for prostate cancer, TTC-MSLN (mesothelioma, pancreatic, and ovarian cancer), and TTC-CD22 (non-Hodgkin lymphoma).
Dr. Morris described the possible use of TTC-PMSA in the treatment of both primary and metastatic prostate cancer. Previous radiotherapy with the beta-emitter Lu177-PMSA617 showed a number of adverse side effects including thrombocytopenia and xerostomia (dry mouth resulting from reduced or absent saliva flow). Some early studies with treatment of prostate cancer with Ac225-PMSA617 showed promising responses by PSA declines and reduction of tumor burden by PSMA imaging but xerostomia is still an issue.
Dr. Morris reported that Phase I clinical trials with TTC-PMSA are beginning now with an anticipated 108 patients. Goals of the study are establishing a safe starting dose and then studying dose escalation. Dr. Morris noted that TAT therapy is typically only begun in metastatic castration-resistant prostate cancer (mCRPC) after androgen deprivation therapy and some combination of abiraterone, enzalutamide, or docetaxel (chemotherapy). Modern trends in prostate treatment indicate moving these later treatments earlier in the treatment cycle. He noted the importance of PSMA imaging which can show metastasis even when a bone scan appears clean. Dr. Morris also pointed out that these new trends could have the desired effect of increasing overall survival (OS) while that control of side effects becomes more important for patient quality of life. It is one thing to ask a patient to endure dry mouth at end of life and quite another to expect the patient to endure xerostomia for ten years
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tango65
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Alpha particles (Ra 223, Ac 225, Th227) have more ionizing radiation than beta particles (Lu 177). They are very effective in destroying targeted cells with less destruction of the surrounding tissues. Ac 225 PSMA is effective in prostate cancer, probably more than Lu 177 PSMA, but it can cause major damge to the salivary glands. They are going to study Th 227 PSMA to determine what dose they should use, if it is effective for the treatment of metastatic prostate cancer and what side effects are caused by this ligand. If it works well it could be an alternative to Ac 225 PSMA and Lu 177 PSMA.
I do not know . I check clinicaltrials.gov but I could not find it. Dr. Morris is a MO from the Memorial Sloan Kettering Cancer Center in NY. Pehaps looking on the web page of the MSKCC or calling them may add some info.
I have just had 4 x Lu177 shots and so far not much of any dry mouth or dry eyes. But other forms of radiation especially IMRT to head and neck area can cause the same dryness of eyes and mouth and often loss of any taste and I have a friend who has dry mouth uses special chewing gum, and there are sprays for tears, and if youse ain't dead because you had the treatment and the cancer is gone, then you'll happily adapt to the side effects. lost all sexual abilities from prolonged ADT and EBRT, so did I jump with Joy? Well no, and in any case at 65 when these things became apparently irreversible, Joy was an old lady petrified by any old man rude enough to point Percy at her, because she'd "paused from men" as a result of her unwanted but inevitable hormone changes to allow her to be a good grandmother without the dramas of dealing with horny men. Its Natural to be forced away from any chance of sex with any willing female and so who else is going to be upset by your dry mouth or eyes?
Its a case of "Suck it up Bro".
The thorium based therapy looks promising but with usual side effects.
It may be awhile before its approved. Meanwhile we have to make do with what is available. Psa before Lu177 was 25, after 4 shots its 3.7, but maybe helped by the last 2 months on enzalutamide, which my doc said would boost the effects of the 2 last Lu177 shots. There's a trial in Sydney to find out if that happens commonly because after many initial trials with only Lu177, docs are trialling combinations of things to see what happens. And in Melbourne at Peter Mac there's a trial for Lu177 to be used for initial primary therapy, and I am guessing but probably for men with high Gleason scores that indicate Pca has already spread, and that it would be no use operating. This was my case. My Psa was low for the huge amount of Pca at PG so I was in-operable and all other treatments that I got with ADT and EBRT and other chemicals did not stop Psa rising. I don't know how long it will be before Psa begins to go up again. I might need more Lu177, if the PsMa Ga 68 scans show enough avidity, but may need Ra225, for the bone mets. I'll only be able to have so much treatment then the day comes when a doc will say "get your affairs in order, there is SFA else in the cupboard"
Damaged salivary glands can make swallowing very difficult. Without natural saliva the peristalsis becomes labored and eating and swallowing are limited. That is a truly serious side effect.
If you are in a position to pay for treatment, I just returned from Homburg Germany where I received PMSA lutetium/actinium therapy for metastatic Prostate cancer. It is not a cure but he has great success with remission, and is the new standard of care for ADT resistant prostate cancer in Germany. Dr Ezziddin is one of the pioneers, and one of the two to use tandem therapy that I know of, the clinic is excellent, the staff competent. The mostly speak English.
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