Advanced Prostate Cancer
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Anyone a Familiar with the Dynamo Trial?

My doctor at MD Anderson recommended me to enter the Dynamo clinical trial when my PSA reaches 2.0. (It is currently 1.4 and is slowly rising from a nadir of undetectable about 18-months ago.) If I don't choose to enter the trial, I will start Zytiga and prednisone when it reaches 2.0.

Attached is the link to the trial. Was hoping that someone on this forum is either a part of the trial or knows something about it. Seems very aggressive, which on one hand I like a lot, but on the other is a bit unnerving.

clinicaltrials.gov/ct2/show...

As a reminder of my background, I was diagnosed in May 2015, PSA 227, Gleason 4+4=8, bone met at T-8 vertebra, been on Lupron since diagnosis, radiation of T-8, 6-rounds of taxotere, PSA was undetectable for a year, and is slowly rising for the last 18 months - about 0.2 every 3-4 months. The radiation also caused me to have a heart electrical issue where my heart rate will not go over 119bpm when exercising. Otherwise in good shape - I exercise, still working.

Appreciate any insights! Hope everyone has a great day!

James

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Interesting study.

Apalutamide [ARN-509] is an anti-androgen, so is used in place of Xtandi, (which itself superseded Casodex).

"It is similar to enzalutamide {Xtandi} both structurally and pharmacologically, acting as a selective competitive antagonist of the androgen receptor (AR), but shows some advantages, including greater potency and several-fold reduced central nervous system permeation." [1]

Phase I study results were published in 2013 [2]:

"ARN-509 was safe and well tolerated, displayed dose-proportional pharmacokinetics, and demonstrated pharmacodynamic and antitumor activity across all dose levels tested. A maximum efficacious dose of 240 mg daily was selected for phase II exploration based on integration of preclinical and clinical data."

A German paper appeared in 2016 [3]:

"[A multicentric, randomized, double-blind, placebo-controlled Phase III study of ARN-509 in men with non-metastatic (M0) castration-resistant prostate cancer (SPARTAN): AUO study AP 82/14]."

This month, another paper looked at the role of androgen receptor [AR] mutations in CRPC men treated with Apalutamide [4]:

"The overall frequency of detected mutations at baseline (7.5%) and progression (7.3%) using the sensitive BEAMing assay was low, suggesting that, based on this assay, AR-LBD mutations such as F877L and T878A are not common contributors to de novo or acquired resistance to apalutamide."

The Anderson trial includes Zytiga (+ prednisone).

I look at antiandrogens & Zytiga as ADT extensions, since all three target the AR in different ways. But there seems to be no continuation of Lupron, e.g. Why allow testosterone to recover while inhibiting DHEA with Zytiga?

In one arm, men will also receive Ipilimumab, which activates the immune system. Note that prednisone is an immunosuppresant!

From a French paper this year [4]:

"Two large studies with ipilimumab, ... reported improved progression-free survival, but not statistically improved overall survival at the primary analysis (CA184 043 and CA184 095)."

"Here, we report on two patients who received ipilimumab in these trials and are still in long-term complete remission with a follow-up of 64 and 52 months respectively after the initiation of ipilimumab."

The other arm will receive Cabazitaxel plus Carboplatin.

Cabazitaxel is a taxane (as is Taxotere). As with Zytiga, it is used with prednisone. Cabazitaxel "is associated with a higher rate of grade ≥3 neutropenia compared with docetaxel {Taxotere}." [5]. "Neutropenia ... is an abnormally low concentration of neutrophils (a type of white blood cell) in the blood." [6]

In a European study [5] (2016):

"Severe neutropenia during cabazitaxel treatment is associated with survival benefit in men with metastatic castration-resistant prostate cancer (mCRPC): A post-hoc analysis of the TROPIC phase III trial."

"Patients with a low NLR at baseline were more likely to develop grade ≥3 neutropenia during cabazitaxel therapy and showed the longest {overall survival}."

{I posted: "Inflammation. [1] Neutrophil-to-Lymphocyte Ratio [NLR]" 8 months ago. The message being that a lower NLR was associated with better results in studies.}

But with neutropenia, one must be careful to avoid bacterial infections. [6]

"Carboplatin in the platinum-based antineoplastic family of medications and works by interfering with duplication of DNA." [7]

There was another study that paired Carboplatin with a taxane [8]:

"Carboplatin plus paclitaxel therapy after docetaxel in men with metastatic castrate resistant prostate cancer."

"Carboplatin/paclitaxel chemotherapy following docetaxel in metastatic CRPC is well tolerated with favorable PSA response rates and survival. This combination is a viable option after progression on docetaxel-based therapy."

As with the PARP inhibitor Lynparza (Olaparib), Carboplatin, by interfering with DNA duplication, may favor men with BRCA2 (& similar) mutations.

"BRCA2-associated, castration-resistant prostate cancer is associated with a higher likelihood of response to carboplatin-based chemotherapy than non-BRCA2-associated prostate cancer." [9]

-Patrick

[1] en.wikipedia.org/wiki/Apalu...

[2] ncbi.nlm.nih.gov/pmc/articl...

[3] ncbi.nlm.nih.gov/pubmed/?te...

[4] ncbi.nlm.nih.gov/pubmed/284...

[5] Inflammation. [1] Neutrophil-to-Lymphocyte Ratio [NLR]

[6] en.wikipedia.org/wiki/Neutr...

[7] en.wikipedia.org/wiki/Carbo...

[8] ncbi.nlm.nih.gov/pubmed/204...

[9] ncbi.nlm.nih.gov/pubmed/286...

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Thanks, Patrick! Appreciate the help!

James

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I am really out of date with the new treatments for Advanced Prostate Cancer developed over the last 7-8 years, however, the use of Predisone as explained to me, and I took 30 mg daily of the stuff for six months during my trial based treatment, is that Predisone has known Prostate Cancer cell killing properties. Oh their are other treatment uses and side effects along with the drug, but I took it solely for this known side effect.

Gourd Dancer

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Yes, prednisone has PCa activity.

With PCa studies that combine a drug with prednisone, there should be a prednisone-only arm.

Here is prednisone as monotherapy:

"Patients with asymptomatic HRPC that were treated with low dose prednisone from April 1998 to 2003 were identified from the British Columbia Cancer Agency patient and pharmacy registries. "

"Forty-nine patients met the inclusion criteria. There was a 22.4% response rate to prednisone as defined by a 50% PSA decline. An additional 16.3% of patients had a PSA decline of < 50%. Ninety percent of patients had no documented side effects. PSA responders were more likely to have bony metastases (9/11 versus 17/38, p = 0.03) and lived longer (24.7 versus 15.4 months median survival p = 0.02). The median duration of response in the PSA responders was 4.3 months (0.89-30). Of all PSA responders, 27% had a time to progression greater than 1 year and 45% did not require chemotherapy for the duration of the study."

(HRPC is CRPC.)

ncbi.nlm.nih.gov/pubmed/171...

-Patrick

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What was dosage of prednisone?

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I also had the DYNAMO option. Instead, we chose to continue Lupron and add Zytiga/Prednisone. After a month, PSA dropped from 12.x to 9.x. Next, we're adding XGEVA and Radium 223. This is all after a clinical trial of nanoparticles of Taxotere. I've lost some of the benefits of DYNAMO, but this is a tailored approach that I favor. Dr. Xxx is familiar with Dr. Meyers and is adopting a similar approach.

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Dr Xxx ???

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Redacted.

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ARN-509, huh? This is what I have to say about those a88holes!!!

I was in a phase 3 study for non-met PCa. When I had imaging done that showed that I had acquired three bone mets, an argument ensued. Did I have mets, or did I not have mets? The West coast was fighting the East coast over this. I was dumbfounded, so I said goodbye to both of them.

Good Luck.

Joe

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