First clinical trial of Lu-177-PSMA-617 in recurrent, hormone-sensitive men

[Tall_Allen]

Some early results of a pilot trial:

prostatecancer.news/2021/04...

[Pwjpp55]

Thanks for posting. Are you aware of any Lu177-PSMA trials, or planning for a trial in the US?

[Tall_Allen in reply to Pwjpp55]

prostatecancer.news/2020/08...

[pilot52 in reply to Pwjpp55]

Ok I will give you my numbers. Dr. Ishta Sen ...Fortis health...Me high tumor volume three rounds . the first two were at 11.84 GBq because of great response last round was reduced to 9.99 GBq. I was chemo naive. Gleason 9 -12 cores, PSA was 13.9. PSMA avid. Bone mets (22)humerus , scapula, spine, pelvis, and one small lymph node. After first infusion psa 3.27 with all but large scapula lesion resolved on psma scan. Following second psa .65 with scapula barely visible on PSMA scan. We reduced the third infusion to 9.99GBq and she felt not external beam radiation would be necessary. My last infusion was Jan 14th. My psa has continued a downward trend reading a 0.2 and no pain. I had extensive preexisting left parotid damage from IMRT for head and neck cancer..( another story , not necessary here) Dr. Sen said my dry mouth would resolve ....guess what ? she was right... Her paper which will be published soon, seems to agree with Tagawa who upon even earlier detection is higher dosage. My friend Charlie had bone mets to spine , Hopkins said he was dead in six years according to their AI calculations ????????had a psa of 0 after first infusion and still remains 0 . We both feel great....I actually have 3 more rounds in the bank if ever needed...Could I have PSMA negative cancer? She does not think so because of 3 indicators which I exhibit. My nadir is looks good. Stop making assumptions off of early clinical trials here. I think Tall Allen simply published them and you guys go crazy....Blue Skies , Sky King and Penny (woof) ......Also still flying a b58 Baron on Angel Flights.....Lowest my PSA has been in years . Who knows I may hit 0.00 on next draw....

[cesces]

1. The combination of your blog with this forum is really powerful.2. Nice questions at the end of your blog.

3. The destruction of salivary gland tissue in a population that already has a heavy pill load seems to me a good reason to avoid psma treatment except as a last resort escalation.

They don't mention kidney damage, but if it is damaging salivary glands it's probably doing some damage to kidneys.

In an aging population a material number of the patients will already have diminishiñg renal capacity.

I am personally dubious about the advisability of psma treatments when adt treatment is still working.

Dry mouth doesn't sound like much, but it has serious long term health consequences.

[pjoshea13 in reply to cesces]

Men with PCa have higher evidence of the metabolic syndrome [MetS] at diagnosis:

"Metabolic syndrome is highly prevalent in patients at risk of prostate cancer and is particularly associated with high-grade prostate cancer." [1a]

"The patients with MetS are diagnosed significantly younger and had higher PSA levels than the other patients. Advanced disease of PCa is seen much more in patients with MetS." [1b]

Men with actual diabetes (at least 12 months) have a lower risk of PCa, but a higher mortality risk if they have PCa.

Men on ADT see an increase in metabolic syndrome markers & a higher risk of progression to diabetes.

... from 2006 ... "data suggest that metabolic syndrome was present in more than 50% of the men undergoing long-term ADT, predisposing them to higher cardiovascular risk." [1c]

"Men with prostate cancer who received ADT are at risk for developing diabetes." [1d]

"Diabetic nephropathy (DN) is one of the most common complications of diabetes mellitus." [2]

"In a cohort of patients with newly diagnosed nonmetastatic prostate cancer, the use of ADT was significantly associated with an increased risk of {acute kidney injury}" [3]

"Renal Function after Radioligand Treatment with 177Lu-PSMA-617" [4]

"Kidneys are exposed to continuous low dose radiation during radioligand therapy with 177Lu-PSMA-617 (Lu-RLT) due to excretion of the ligand and specific binding. This may result in glomerular damage and gradual renal function loss."

"Slight reduction in renal function may be expected in patients undergoing radioligand therapy with 177Lu-PSMA-617 and correlates with cumulative doses. Acute kidney injury was observed only in a small number of cases with subrenal obstruction."

Seems that one should check out the kidneys before making a decision about 177Lu-PSMA-617.

-Patrick

[1a] pubmed.ncbi.nlm.nih.gov/327...

[1b] pubmed.ncbi.nlm.nih.gov/309...

[1c] pubmed.ncbi.nlm.nih.gov/169...

[1d] pubmed.ncbi.nlm.nih.gov/299...

[2] pubmed.ncbi.nlm.nih.gov/339...

[3] pubmed.ncbi.nlm.nih.gov/238...

[4] jnm.snmjournals.org/content...

[cesanon in reply to pjoshea13]

1. "Seems that one should check out the kidneys before making a decision about 177Lu-PSMA-617" pjoshea13

That makes good sense to me.

2. The correlation & plausible cause and effect between and among ADT, MetS, Diabetes, and PCA seem confusing and counterintuitive to my mind:

(a) Association of MetS with PCA: "Metabolic syndrome is highly prevalent in patients at risk of prostate cancer and is particularly associated with high-grade prostate cancer." [1a]

(b) More Association of MetS with PCA: "The patients with MetS are diagnosed significantly younger and had higher PSA levels than the other patients. Advanced disease of PCa is seen much more in patients with MetS." [1b]

(c) Non-Association of PCA with Diabetes: "Men with actual diabetes (at least 12 months) have a lower risk of PCa, but a higher mortality risk if they have PCa."

(d) Confounding Variables (ADT/MetS/Diabetes): "Men on ADT see an increase in metabolic syndrome markers & a higher risk of progression to diabetes."

Does anyone have any conjectures or partial conjectures as to the cause, effect, and mechanisms at play here?

[Tall_Allen in reply to cesanon]

There was no diabetes or metabolic syndrome noted - why are you even bringing it up?

[pjoshea13 in reply to cesanon]

I think that insulin is the issue. Many men entering the PCa years have some degree of insulin resistance. A surrogate test for insulin resistance is the triglycerides:HDL ratio. High triglycerides & low HDL are two of the five symptoms of MetS. We only need one other to be classified as having MetS. Choose from: abdominal obesity, high blood pressure & high blood sugar. Elevated glucose goes along with insulin resistance.

A large percentage of such men are pre-diabetic & remain so. Insulin resistance means that their beta cells try to overcome resistance by secreting more & more insulin. With diabetes, beta cells have died off from exhaustion and insulin levels fall.

Diabetics have more cancer risk, of every type except PCa. That's an amazing fact (which some have attempted to explain away.) I believed it is because they have "solved" the insulin problem. It takes about a year for PCa risk reduction to become apparent. {Diabetics receive treatment; pre-diabetics mostly don't.} The standard initial treatment for diabetes is Metformin & education about avoiding glucose spikes & reducing the need for high levels of insulin. Many will have moved on to another medication - plus Metformin - by the end of the first year. For men who are not diabetic, I think it wise to eat as though one is. Low-carb as in the Mediterranean Diet. 40% fat at each meal/snack will soften the postprandial glucose climb.

I have blood results after 3 months of testosterone & after 3 months of castration. My triglycerides jump from ~50 to ~115. ADT inevitably moves one towards MetS, & those with MetS towards diabetes.

It's unfortunate that insulin appears to be a risk factor for PCa (& PCa mortality) & that the standard treatment (ADT) promotes elevated levels.

"Plasma insulin concentration is increased in prostate cancer patients during androgen deprivation therapy (ADT) and hyperinsulinemia has been associated with aggressive prostate cancer behavior." [1]

"The current data suggested that men with PCa who are receiving long-term ADT are at risk for developing insulin resistance and hyperglycemia, thus leading to their increased risk of cardiovascular disease. This adverse metabolic profile developed independent of age and BMI and appeared to be a direct result of androgen deprivation." [2]

"... our findings support the hypothesis that the elevated insulin levels associated with therapeutic castration may exacerbate progression of prostate cancer to incurable CRPC in part by enhancing steroidogenesis." [3]

-Patrick

[1] pubmed.ncbi.nlm.nih.gov/205...

[2] pubmed.ncbi.nlm.nih.gov/163...

[3] pubmed.ncbi.nlm.nih.gov/217...

[GeorgeGlass in reply to pjoshea13]

Very good analysis

[Tall_Allen in reply to cesces]

Salivary gland problems were not an issue at these low doses. The dry mouth cases were mild and transient, no long term issues. No kidney problems, mainly some short-term fatigue, as I said.

[GeorgeGlass in reply to Tall_Allen]

That’s what pilot said from his experience. A couple doctors offered me to join a Ra-225 trial but i said no. Pilot told me it’s stronger than lu177. The 225 will probably cause permanent salivary gland damage.

[Ahk1]

Thanks a lot, TA for posting and summarizing all of this for us. We do appreciate it. I would have been qualified if I didn’t start ADT 6 months ago. I might have missed something in your article but it didn’t look promising to me compared with just ADT. Lots of nice questions you outlined and hope it adds to the tools we have to fight this disease. Thanks again.

[Tall_Allen in reply to Ahk1]

It was a very small study on men who were progressing rapidly, and a light dose was used. I hope they are able to identify characteristics of the responders.

[wpopomaronis]

Thank you

[Fairwind]

I was in the Vision trial. Did all 6 treatments. It worked great at first, PSA dropped rapidly. But after my 6th treatment, PSA started to climb again (over 2000 now) and blood counts dropped to critical levels requiring multiple transfusions of whole blood. I've been fighting this for 20 years but there is not much fight left in me.. Seems like the radiation destroyed my bone marrow..

[Tall_Allen in reply to Fairwind]

The radiation and the cancer itself destroys bone marrow, sadly. I think that's one of the reasons they used such low doses in this trial.

[Ahk1 in reply to Tall_Allen]

Does the SRT(IMRT) also destroys the bone marrow? Thanks.

[Tall_Allen in reply to Ahk1]

No. It stimulates T cells.

[tayninhtom]

Thanks for the research, interesting statistics.

[Costarica1961]

Thankyou i am currently being treated with cabataxal and carboplatin, I am going on treatment #12 which i understand is a lot for this combination. My Psa is down incrementally from 243 to 6.9, my labs have been marginally good. Am I a candidate for Lu 177 with a psa moving downward.

[Tall_Allen in reply to Costarica1961]

It depends on how PSMA-avid your cancer is.

[Costarica1961 in reply to Tall_Allen]

Ok Thank-you