Predicting BAT efficacy

[PCaWarrior]

JH has a special assay. Not available to the public.

Predicting Efficacy of Bipolar Androgen Therapy (BAT) in Prostate Cancer

Key Predictive Biomarkers and Mechanisms

Based on recent clinical trials and mechanistic studies, the following factors predict BAT efficacy:

Biomarker/Mechanism Predictive Value Evidence Source

AR Alterations in ctDNA Patients with AR amplification or mutations (e.g., T878A, L702H) benefit from BAT. TRANSFORMER Trial (ASCO 2024): 53% of patients with AR alterations in ctDNA had improved PFS/OS vs. Enzalutamide. No AR alterations → worse outcomes on BAT.

High AR Activity (ARA MW Score) ARA MW score >0.6 (gene signature of AR activity) predicts tumor regression and survival. PMC9711876: High AR activity drives MYC suppression. Patients with ARA MW >0.6 had median OS of 47.4 vs. 29.0 months (low AR activity).

MYC Downregulation BAT-induced MYC suppression correlates with clinical response. Preclinical/clinical data: High AR activity enables MYC suppression, reducing proliferation.

Low Tumor-Suppressor Loss BAT + PARPi may benefit patients with BRCA2/P53 loss (preclinical synergy). ScienceDirect Study: Combined tumor-suppressor loss (e.g., BRCA2/P53) linked to BAT resistance; PARPi may resensitize.

Clinical Implications

Patient Selection:

• Favorable: AR alterations (ctDNA), high AR activity (ARA MW >0.6), MYC overexpression.

• Unfavorable: No AR alterations, low AR activity, tumor-suppressor loss (BRCA2/P53).

Recommendations

• Use ctDNA to detect AR alterations (amplifications/mutations) and calculate ARA MW score.

• Prioritize BAT for AR-altered/high AR activity tumors.

Therapeutic Strategies:

• For AR-altered tumors: BAT ± immunotherapy (BATRAD trial).

• For AR-wild-type tumors: Enzalutamide or combination therapies (e.g., PARPi + BAT).

Conclusion

BAT efficacy is predictable via AR status and activity biomarkers. Patients with AR-driven tumors (ctDNA alterations, high ARA MW score) derive significant benefit, while others should receive alternative therapies. Ongoing trials (e.g., STEP-UP, BATRAD) aim to optimize sequencing and combinations.

Grade of Evidence: B (Phase II/III trial data, validated preclinical models).

References:

1. TRANSFORMER Trial (ASCO 2024)

Title: Blood-Based Markers of Differential Efficacy of Bipolar Androgen Therapy and Enzalutamide in the Randomized TRANSFORMER Trial

URL: ASCO 2024 Abstract

2. Sena et al. (PMC9711876)

Title: Androgen receptor activity in prostate cancer dictates efficacy of bipolar androgen therapy through MYC

URL: PMC9711876

3. ScienceDirect Study (Tumor-Suppressor Loss)

Title: Clinical Efficacy of Bipolar Androgen Therapy in Men with Metastatic Castration-Resistant Prostate Cancer and Combined Tumor-Suppressor Loss

URL: ScienceDirect Article

[podsart]

if one has failed 1 or more AR blockers [xtandi, apalutamide], can you impute that you probably have AR altered tumors referenced above?

[PCaWarrior in reply to podsart]

10% me and 90% from Perplexity Deep Research:

Implications of Failing Multiple AR Blockers in Prostate Cancer

Key Conclusion

Failure of ≥1 AR blocker (enzalutamide, darolutamide, abiraterone, apalutamide) strongly suggests AR alterations in prostate cancer. Clinical studies show:

55–65% of patients progressing on AR blockers develop AR mutations, amplifications, or splice variants.

AR amplification occurs in 55.4% of progressing patients vs. 5.3% of responders.

AR-V7 (splice variant) is detected in 39% of enzalutamide-resistant and 19% of abiraterone-resistant tumors.

AR Alterations Linked to Treatment Failure

Mechanism Prevalence Post-AR Blockers Impact

AR Amplification 35–55% Overcomes drug antagonism via receptor overload

AR Mutations 18–24.5% Alters drug binding (e.g., F877L confers enzalutamide resistance)

AR Splice Variants (AR-V7) 20–39% Enables ligand-independent AR signaling

Intratumoral Androgen Synthesis 15–30% Reactivates AR via local testosterone/DHT production

Cross-Resistance Between AR Blockers

Shared Resistance Pathways:

AR amplification/mutations reduce efficacy of all AR blockers (enzalutamide, darolutamide, etc.).

AR-V7 confers resistance to enzalutamide/abiraterone but retains taxane sensitivity.

Sequential Failure Data:

Abiraterone → Enzalutamide: Only 15–44% PSA50 response.

Enzalutamide → Abiraterone: ≤3% PSA50 response.

Darolutamide: Effective against some AR mutants (e.g., F876L) but not AR-V7.

Clinical Implications

Genetic Testing Recommended:

Liquid Biopsy: Detect AR mutations (L702H, T878A, F877L) and AR-V7 in circulating tumor DNA.

Tissue Testing: Identify AR amplification via FISH or NGS.

Treatment Adjustments:

AR-Altered Tumors:

Switch to taxanes (docetaxel/cabazitaxel).

Consider PARP inhibitors if BRCA1/2+.

Lutetium-177 PSMA-617 radiopharmaceutical therapy.

AR-Independent Tumors:

Platinum chemotherapy (cisplatin/carboplatin) for neuroendocrine differentiation.

Immune checkpoint inhibitors if MSI-H/dMMR.

Limitations

Not All Resistance is AR-Driven: 20–40% of cases involve non-AR mechanisms (e.g., neuroendocrine differentiation, PI3K/AKT activation).

AR-V7 False Negatives: Current assays miss 10–15% of splice variants.

Actionable Steps

Confirm AR status via cfDNA/tissue testing.

Prioritize non-AR therapies (taxanes, PARPi, radiopharmaceuticals) or BAT.

Explore clinical trials targeting AR variants (e.g., EPI-7386 for AR N-terminal domain).

Bottom Line: Failure of ≥2 AR blockers strongly predicts AR-driven resistance. Precision testing and AR-independent therapies are critical next steps.

55–65% of patients progressing on AR blockers develop AR mutations, amplifications, or splice variants.

AR amplification occurs in 55.4% of progressing patients vs. 5.3% of responders.

AR-V7 (splice variant) is detected in 39% of enzalutamide-resistant and 19% of abiraterone-resistant tumors.

AR Alterations Linked to Treatment Failure

Mechanism Prevalence Post-AR Blockers Impact

AR Amplification 35–55% Overcomes drug antagonism via receptor overload

AR Mutations 18–24.5% Alters drug binding (e.g., F877L confers enzalutamide resistance)

AR Splice Variants (AR-V7) 20–39% Enables ligand-independent AR signaling

Intratumoral Androgen Synthesis 15–30% Reactivates AR via local testosterone/DHT production

Cross-Resistance Between AR Blockers

Shared Resistance Pathways:

AR amplification/mutations reduce efficacy of all AR blockers (enzalutamide, darolutamide, etc.).

AR-V7 confers resistance to enzalutamide/abiraterone but retains taxane sensitivity.

Sequential Failure Data:

Abiraterone → Enzalutamide: Only 15–44% PSA50 response.

Enzalutamide → Abiraterone: ≤3% PSA50 response.

Darolutamide: Effective against some AR mutants (e.g., F876L) but not AR-V7.

Clinical Implications

Genetic Testing Recommended:

Liquid Biopsy: Detect AR mutations (L702H, T878A, F877L) and AR-V7 in circulating tumor DNA.

Tissue Testing: Identify AR amplification via FISH or NGS.

Treatment Adjustments:

AR-Altered Tumors:

Switch to taxanes (docetaxel/cabazitaxel).

Consider PARP inhibitors if BRCA1/2+. Or PARP inhibitors with BAT or RT or SBRT regardless of BRCA status.

BAT

Lutetium-177 PSMA-617 radiopharmaceutical therapy.

AR-Independent Tumors:

Platinum chemotherapy (cisplatin/carboplatin) for neuroendocrine differentiation.

Immune checkpoint inhibitors if MSI-H/dMMR.

Limitations

Not All Resistance is AR-Driven: 20–40% of cases involve non-AR mechanisms (e.g., neuroendocrine differentiation, PI3K/AKT activation).

AR-V7 False Negatives: Current assays miss 10–15% of splice variants.

Actionable Steps

Confirm AR status via cfDNA/tissue testing.

Explore clinical trials targeting AR variants (e.g., EPI-7386 for AR N-terminal domain).

Or try to resensitize (e.g. BAT)

[dhccpa]

Have you had the JH test done?

[PCaWarrior in reply to dhccpa]

No. I'd likely need to be in a clinical trial.

[Professorgary in reply to dhccpa]

I just recently had an appointment with Denmeade to discuss the possibility of BAT and asked him about this mysterious test available to only JHUH patients. He told me that there was no magic test but a great deal of things that could be helpful in predicting if a patient would respond. One was a particular gene mutation. As far as not being available to the public, how did I just read it then? From what I gathered from our discussion I could be a good candidate because I am asymptomatic and responded extremely well to lupron, 5664 down to 278 in 3 weeks and abiraterone, 19.9 down to 4.79 in 3 weeks.

Denmeade works with doctors worldwide in an effort to help patients that might benefit from BAT. He will not however directly treat any patient that he doesn’t see face to face for the first time. After that he will do video visits if you live in a state that he is licensed in.

He just switched me from prednisone to dexamethasone so well see if I respond but if not BAT will be my next treatment. Just like bat, prednisone to dexamethasone has certain predictors which are favorable in my case so next Thursday’s blood test will tell.

[PCaWarrior in reply to Professorgary]

What are the predictors for pred->dexa swith?

I asked Denmeade about the JH ARA MW test last week and he said it wasn't available to the public. Only at JH in their labs. I even have a procedure to do it. Complicated and the weighting of different variables is proprietary. So the info is useless to me.

I think to get it you'd need to be part of a JH clinical trial or perhaps a research study.

When did Denmeade say that they don't have the ARA MW test?

[Professorgary in reply to PCaWarrior]

Answer to first question. Psa lower than 50, 6 months or less before abi starts to fail and alp less than 160 were all prognistic indicators. These were all independent of each other. Next question, he never said anything about any specific test. Only that there was not a single test that could accurately predict response to BAT. I think he was saying that there were several test that combined would give a very clear picture. Some with genetic mutations could respond well but some without those mutations but a high number of androgen receptors could also respond well. He also said tissue biopsies tell a better story than blood tests but guys don’t care to have tissue biopsies on a regular basis. Also, any test that is BAT specific as a diagnostic tool would probably not be covered be insurance sinceBAT is not FDA approved.

[PCaWarrior in reply to Professorgary]

Thanks. I put the "Psa lower than 50, 6 months or less before abi starts to fail and alp less than 160 were all prognistic indicators. " criteria into my book (possible indication of increased success rate).

[Professorgary in reply to PCaWarrior]

According to Denmeade the issue is that after time certain gut bacteria can cause the prednisone to form a testosterone like molecule which can feed the cancer. I really don’t think the dexamethasone is as much of a benefit as just stopping prednisone is. In the near future I plan on discussing the possibility of stopping steroid use. It can and has been done by monitoring the side effects caused by adt and treating them individually with the appropriate meds. Here is a pic of what Denmeade said about the possible benefit from switching from pred to dex.r

R

[PCaWarrior in reply to Professorgary]

Thanks!

[dhccpa in reply to Professorgary]

Thank you. Very good info.

[dhccpa in reply to Professorgary]

Just for the record, Florida seems to allow video visits with out of state doctors if they register properly with the state.

flboardofmedicine.gov/licen...

[Professorgary in reply to dhccpa]

Great to know. When I read the patient reviews of Denmeade one guy said he drove a thousand miles to see him and finished with “that should tell you something” , or something to that effect. When I had my first visit he required the first visit to be face to face but I can now do video visits.

[PCaWarrior in reply to Professorgary]

I know a couple of guys that drove halfway across the country to see Denmeade.

[MateoBeach]

this provides much clarity that has been needed. Question: Does the genetic information currently provided in current FDA approved ctDNA tests permit calculation of ARA MW scores? Or is this currently unavailable in the community?

[PCaWarrior in reply to MateoBeach]

You can get an idea of what the activity is. But the actual ARA MW score is proprietary. I think you'd need to be in a JH clinical trial and check with the chief investigator.

There are procedures to sort of approximate it in a way, but they are ridiculously complex.

[PCaWarrior in reply to MateoBeach]

Actually, quite straightforward and easy to calculate.

To calculate the ARA MW score (Androgen Receptor Activity Molecular Weighted score) for predicting Bipolar Androgen Therapy (BAT) efficacy in prostate cancer, the process involves analyzing gene expression signatures associated with androgen receptor (AR) activity. Based on the referenced study (PMC9711876) and standard methodologies for AR activity scoring, here's the general framework:

Steps to Calculate the ARA MW Score

1. Gene Signature Selection:

• Use a predefined panel of AR-regulated genes (e.g., KLK3 [PSA], TMPRSS2, NKX3-1, FOLH1 [PSMA], MYC).

• These genes are validated biomarkers of AR transcriptional activity.

2. Gene Expression Measurement:

• Extract RNA from tumor tissue or liquid biopsy (e.g., ctDNA).

• Quantify expression levels via RNA sequencing, NanoString, or qPCR.

3. Normalization:

• Normalize expression values to housekeeping genes (e.g., GAPDH, ACTB) to account for sample variability.

4. Weighted Summation:

• Apply gene-specific weights (derived from regression models correlating gene expression with AR activity or clinical outcomes):

ARA MW Score=∑i=1n(wi×Normalized Expressioni)ARA MW Score=i=1∑n(wi×Normalized Expressioni)

• Example weights (hypothetical):

• KLK3: 0.4

• TMPRSS2: 0.3

• MYC: 0.2

• NKX3-1: 0.1

5. Thresholding:

• ARA MW > 0.6: High AR activity → predicts BAT efficacy (median OS: 47.4 vs. 29.0 months for low activity).

• ARA MW ≤ 0.6: Low AR activity → BAT resistance likely.

Key Insights from the PMC9711876 Study

• Mechanistic Basis: High AR activity suppresses MYC oncogene expression, enhancing BAT-induced tumor regression.

• Clinical Validation: Patients with ARA MW > 0.6 had significantly improved survival outcomes on BAT.

Practical Considerations

• ctDNA vs. Tissue: While tissue biopsies are ideal, ctDNA-based AR amplification/mutation analysis can proxy AR activity (e.g., AR-V7 detection).

• Commercial Assays: Some labs offer validated AR activity panels (e.g., Decipher AR-Activity Score).

Confusion Clarification

• ARA Algorithm/Other Acronyms*: The term "ARA" in this context refers to Androgen Receptor Activity, not the unrelated ARA* algorithm or rental metrics.

For precise gene lists, weights, and validation cohorts, consult PMC9711876 or clinical AR activity assays.

[Professorgary in reply to PCaWarrior]

Im just gonna play the devils advocate here for a second. While BAT is in the clinical trial stages at JHUH, could it be possible that they don’t want to eliminate you from the clinical trial by doing the test you are talking about. They may want both type patients, both responders and nonresponders to further validate the process to determine non responders in order to present a valid case before the FDA.

When Denmeade offered me the clinical trial and discussed the different arms at no time did he offer any testing before the trial but said testing would be done during the trial. This is now starting to make sense as to why he didn’t want me to be tested first. Why eliminate a potential test subject and taint the study results by cherrypicking test subjects.

[PCaWarrior in reply to Professorgary]

You play a good devil.

I think the truth is probably less nefarious. They aren't very confident in the test's predictive powers. Denmeade, like most doctors, is quite cautious. Being cautious and only wanting to rely on proven things, is he likely to turn guys away based on the results of an unproven test? If this or some other test is validated, he'll use it.

Also, I'm guessing they do not know whether the test can "predict" someone's response or if the delta in results during treatment is the key. We know that ARs are downregulated and then upregulated during BAT. Maybe it's the men who display high change that do better?

One final thought, and I'll let you get back to the busy life of a demon: Denmeade is trying to get the therapy into SOC. If he was confident that he could cherry-pick good candidates for BAT, the results of his trials would improve. And the guys who would score higher on the ARA MW test should also do worse than average on Xtandi.

[Professorgary in reply to PCaWarrior]

Makes sense. Now please don’t let my screen name give you the idea that I am a professor or even highly educated. I’m a high school graduate, barely 😂. So, that word you just used “nefarious” yea, I have no clue. Great chatting with you. God bless.

[PCaWarrior in reply to Professorgary]

Lol! Nefarious. You apparently didn't watch a lot of Rocky and Bullwinkle. Dastardly (Dastardley and Mutley).

Have a good one.

God bless.

[Watcher24]

In my case the ARA mw unfortunately is low, BAT alone does not work. BUT, after a month on BAT the cells are resensitized, Daro brings the PSA back. AR-V7 is removed. I follow the dynamic STEP-UP pattern.

[PCaWarrior in reply to Watcher24]

Nice! Are you in the trial? I guess not because you're using Nubeqa. Is Denmeade guiding it?

[Watcher24 in reply to PCaWarrior]

No, I live in Oslo Norway, my MD lets me decide on the treatment.

[PCaWarrior in reply to Watcher24]

How are things going for you?