225Ac-PSMA-I&T works well even after Pluvicto in small trial

[Tall_Allen]

It's small number of heavily-treated mCRPC patients, but 42% of those who already had Pluvicto had a PSA reduction of ≥50% from 225Ac-PSMA-I&T. Surprisingly, no Grade 3 Xerostomia.

Phase III trials will likely follow.

prnewswire.com/news-release...

[KocoPr]

That is really great news for all of us!

Questions: what is a “superscan patient”?

Found this also.

Definition: Superscan is defined as “a bone scan which demonstrates markedly increased skeletal radioisotope uptake relative to soft tissues in association with absent or faint renal activity (absent kidney sign).” Superscan was first described by Osmond et al.

I looked but can’t find what the I&T mean. Anyone know? I found it (Imaging and Therapy (I&T))

PI-2265 Phase 2/3 Development Program in mCRPC

Fusion is advancing a Phase 2/3 trial for FPI-2265 in patients with mCRPC with progressive disease who have previously been treated with a 177Lu-based PSMA radiotherapy. The Phase 2 portion is expected to be initiated in the second quarter of 2024. A Phase 3 global registrational trial is expected to begin in 2025 following analysis of the Phase 2 data and an end of Phase 2 meeting to align with FDA on the recommended Phase 3 dosing regimen.

————————

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

Several studies using [177Lu]Lu-PSMA-617 and [177Lu]Lu-PSMA-I&T as a therapy have shown to be very effective in treating PCa [7,8,9,10,11,12,13,14,15,16], while at the same time being well tolerated, with minor side effects. It is expected that an alpha-emitter would be even more effective than a beta-emitter, such as [177Lu]Lu-PSMA. The use of alpha-emission offers advantages over beta-emission due to the high linear energy transfer (LET) and the limited range in tissue [17]. The high LET effectively kills tumor cells through DNA double-strand and DNA cluster breaks, and the limited range allows selective tumor cell killing while sparing healthy tissue [18,19]. In the past few years, the alpha-emitting radionuclide Ac-225 has been subject to several investigations as a potential radionuclide in targeted alpha therapy (TAT). Ac-225 is an alpha emitter with a half-life of 9.92 days, which is an appropriate half-life for convenient treatment. Decay of Ac-225 occurs via a cascade ending into stable Bismuth-209 (Bi-209) via six short-lived daughter radionuclides and emission of four alpha particles. Total energies of alpha-particles range from 5.8 to 8.4 MeV with tissue ranges of 47 to 85 µm. The cascade also includes two beta-disintegrations of 1.6 and 0.6 MeV, and minor gamma co-emissions are generated from disintegrations of Fransium-221 (Fr-221) and Bismuth-213 (Bi-213), which can be used for detection [20].

[Tall_Allen in reply to KocoPr]

Superscan is when the bone scan lights up everywhere. It means the cancer is in all bones and bone marrow.

I&T (Imaging and Therapy) is a ligand (a part of the drug molecule) that attaches to the PSMA protein on the cancer cell. Pluvicto uses a different ligand, PSMA-617, for therapy. For imaging, they use a different ligand, PSMA-11, with Ga-68. The ligand is what makes the drug more or less specific.

[KocoPr]

Also I understand this 225Ac with its much larger longer half life will make it easier to be distributed throughout the country and worldwide.

This is a game changer!

[SeosamhM in reply to KocoPr]

Sorry, KocoPr, while it certainly seems to me that 225Ac would be a nice addition to the arsenal, it looks like 225Ac is technically tough to produce. See: ncbi.nlm.nih.gov/pmc/articl...

[KocoPr in reply to SeosamhM]

Thanks for correcting me. I just read your article and a new 2024 article on the production and administration as a pharmaceutical.

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

Implementing Ac-225 labelled radiopharmaceuticals: practical considerations and (pre-)clinical perspectives

[Tall_Allen in reply to SeosamhM]

Obviously, they produce enough for trials. They have time to develop manufacturing facilities to meet demand if it gets approved after Phase 3 (beginning in 2025).

[SeosamhM in reply to Tall_Allen]

I don't disagree, I am just conservative. While its been almost 20 years since my graduate studies in radiochemistry, after a dip into the literature it is pretty clear to me that the manufacture of 225Ac for radiopharmaceuticals (isotopically pure) is extremely challenging and will remain so until novel nuclear techniques are developed. This goes for most of the (limited by safety) candidates (e.g., Ac, Bi, Pb...) for targeted alpha radiation therapy (TAT).

[NOCanceros]

Hello Tall_Allen

Thanks for everything you write , I have no idea about these things, just Iam happy to read your information.

[God_Loves_Me]

Sorry I do not mean to change the topic, I am not sure what's the best way to ask you questions directly. Have you study Terbium-161 ? I heard good things but haven't seen any news recently

[SeosamhM in reply to God_Loves_Me]

Studies on 161Tb are ongoing in Switzerland, Germany, and Australia. See: link.springer.com/article/10.1007/s00259-023-06316-y

Truly, the PSMA ligand has opened up an expanse of opportunities for aPCa treatment.

[Tall_Allen in reply to God_Loves_Me]

There are many radioisotopes and many ligands being explored in clinical trials. It takes many years to prove safety and efficacy. There are lots of "good things" to be hopeful about. In the US, these trials are the furthest along:

prostatecancer.news/2020/08...

[gsun]

Act has always been more effective but there are side effects that are difficult.

youtu.be/8DkhSFS0FY4(Not working as expected?)

[Tall_Allen in reply to gsun]

That’s why the low xerostomia is so surprising and good.

[gsun]

They report grade one and two xerostomia. Is that out of three? they didn't say if the patients got better or not and in what time frame? Why did they recruit prior Pluvicto treated patients? Act is a better therapy and it looks like Pluvicto naive patients did better.

[Tall_Allen in reply to gsun]

Grading is 1-5. Grade 1 is mild, Grade 2 is annoying, but no intervention required. It was temporary.

The recruitment was for heavily pretreated patients, which is why many had already had Pluvicto.

You expect Pluvicto-naive to have a greater response to their first PSMA-targeted therapy, compared to a second go at the same protein biomarker. The fact that even the second try was so big is very promising.

[dmt1121]

Looks promising.

[Islandboy2021]

it’s promising to here that there could be future treatment opportunities for men with advanced disease.

Thanks for posting.