Advanced Prostate Cancer
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Mechanism for Provenge suggested

There has not been an accepted explanation for the results of the Provenge trials - IMPACT being the main one. But the notion has been that "the data is the data", and the rationale, the mechanism of action, will become evident as time goes on. Part of the puzzle, the puzzling part, is that Provenge did not prolong progression free survival, did not delay progression, but did extend overall survival compared to placebo, the placebo arm. And people who were on the placebo arm, if they progressed and decided to cross-over, did better than those who did not cross-over. The cross=over consisted in the reinfusion of white cells previously extracted, in a product cleverly called Frovenge - frozen Provenge.

These treatments did not have an effect on PSA.

[PSA is created in the prostate cells when the Androgen Receptor, a transcription factor, moves into the nucleus and binds near the gene for PSA and expresses that gene - ie creates the mRNA that is edited and exits the nucleus, enters the ribosome and where the PSA protein is constructed very rapidly out of material delivered by tRNA. Made by magic essentially.]

That is to say that Provenge does not seem to have an effect on the activity of the Androgen Receptor as reflected by PSA.

Rather than being a medicine in the Androgen Receptor line of treatments, its approach is to try to get the body to see PAP as a foreign molecule, to see PAP as an antigen, and so to turn against this chemical.

So while prostate cancer can be attacked by using its prostate features or its cancer features, Provenge, like ADT, seems to focus on the prostate features, but not on the AR; not on the hormone mechanism that ADT uses.

Another clue, as to how it works, is that Provenge seems to work better in older men than younger men, according to one analysis of the IMPACT data released. It seems to not work at all, in fact, in younger men (<65), as opposed to the matching group in the placebo arm, is the claim.

Martin002

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Here is an analysis of the released data that provides an hypothesis of the mechanism of action, called "understanding the Provenge trials".

theprovengetrials.org/pages...

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I watch.

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The most well understood lines of immune therapy are 1) anti-bodies (like CimaVax against EGF, and herceptin en.wikipedia.org/wiki/Trast... )

and 2) antigen presenting cells (like CAR-T).

Provenge claims to be aimed at PAP, but uses neither of these two natural mechanisms, and has no explanation as to whatever it thinks it is doing. Plus, your blood has levels of PAP that can be measured, and are measured. I don't know of anyone who wants to get rid of PAP in the blood, yet it also seems to me that that would be the first target of an recruited immune response. Bloodlevels of PAP should drop to zero. The real target of course is the cell with PAP expressed on its membrane, thinking that these must be prostate cancer cells. Is that in fact true? Are they, and are they being targeted by the immune system post treatment? Dendrion is very far from making that claim or that case.

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Regarding a PSA response:

In a 2000 Phase I/II study [1]:

"Three patients had a more than 50% decline in prostate-specific antigen (PSA) level, and another three patients had 25% to 49% decreases in PSA."

From a 2004 paper [2]:

"Two patients exhibited a transient 25-50% decrease in prostate-specific antigen (PSA). For a third patient, PSA dropped from 221 ng/ml at baseline to undetectable levels by week 24 and has remained so for more than 4 years."

From 2005 [3]:

"Thirteen of 18 patients demonstrated an increase in PSA doubling time (PSADT), with a median increase of 62% (4.9 months before treatment vs. 7.9 months after treatment"

From a Phase III trial paper (2009) [4]:

"Of the 147 patients in the sipuleucel-T arms, 5 patients had a PSA reduction of ≥50% confirmed on a second occasion at least 4 weeks later, and an additional 2 patients had confirmed PSA reduction of ≥25%, for an overall PSA response rate of 4.8%. None of the 78 patients on the placebo arms had confirmed PSA reductions of 25% or more. The PSA response rate may be underestimated, as PSAs were only collected at baseline, Week 16, and then every 16 weeks thereafter until disease progression, and only 26% of patients had ≥2 PSA values at least 4 weeks apart."

...

Also from [4]:

"In a randomized phase 3 study, D9901, sipuleucel-T treatment has previously been shown to provide a survival benefit as well as a trend toward a delay in time to disease progression in men with metastatic AIPC. A second randomized phase 3 study, D9902A, demonstrated a trend toward improved overall survival. The lack of statistical significance and a smaller observed treatment effect for overall survival in D9902A may have been in part attributable to the smaller sample size; the trial was stopped early and resulted in 26% fewer death events than D9901. In addition, baseline prognostic factors in D9902A were less well balanced than in D9901. After adjustment for baseline prognostic factors, the survival treatment effect in D9902A was comparable to that observed in D9901.

"To provide an estimate of the overall sipuleucel-T treatment effect in this patient population, we performed an integrated analysis of D9901 and D9902A. This analysis allowed us to include all patients from both randomized studies in AIPC with identical eligibility criteria as well as incorporate potential study to study variability.

"In the integrated analysis of D9901 and D9902A, we observed a trend toward a delay in the time to disease progression. The rapid rate of disease progression in these studies likely made it more challenging to demonstrate an effect on the disease progression endpoint. At the time D9901 and D9902A were designed, it was anticipated that the target population of patients with asymptomatic, metastatic AIPC would progress more slowly than patients with symptomatic disease, thereby allowing more time for the immunotherapy to take effect. This assumption proved incorrect, with the median time to disease progression being comparable to that observed in symptomatic patients"

"Overall survival may be a more appropriate endpoint for advanced prostate cancer trials, because death events generally occur much later than progression events, allowing more time for the therapy to take effect, particularly for immunotherapeutic agents such as sipuleucel-T. The 33% reduction in the risk of death, the 4.3-month median survival difference, and the >100% increase in the 36-month overall survival rate of men treated with sipuleucel-T compared with placebo demonstrate the potential clinical significance of the treatment effect. The treatment effect was observed despite the presence of a crossover trial design, in which 72% of patients randomized to placebo received salvage therapy with a version of sipuleucel-T made from cells cryopreserved at the time of placebo manufacture. Importantly, the survival benefit remained strong after adjusting for baseline prognostic factors in a multiple regression model. Additional analyses suggest that the survival benefit cannot be explained by an imbalance in the timing or use of chemotherapy after study treatment, or by an imbalance in nonprostate cancer-related deaths."

-Patrick

[1] ncbi.nlm.nih.gov/pubmed/110...

[2] ncbi.nlm.nih.gov/pubmed/151...

[3] ncbi.nlm.nih.gov/pubmed/159...

[4] onlinelibrary.wiley.com/doi...

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thanks for looking at it.

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But those texts do not address the claim that age was a key factor in response, that those under 65 showed no statistical benefit. and those over 65, the age group for whom the treatment worked, unexpectedly had a shorter overall survival that those under 65, for whom the treatment did not work.

That is the claim of the counter analysis.

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Provenge has the reputation for not lowering PSA.

prostatesnatchers.blogspot....

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