SARMS, Anabolic, androgen etc..

[Yzinger]

Hi all. Reminder im a PCa brother, been through the chemo and radiation and now living in 3mth intervals 😀 waiting on PSA results.

Although I'm extremely thankful to be alive and fighting im trying to research ways we might STILL be able to look good naked. I know we see posts now and then about SARMS and ostarine in particular but I'm trying to understand it all.

We need to keep natural test low and I assume synthetic test would also he bad. Aas would increase test and thus not for us...but aas are anabolic in nature. Would androgenic products work for us?

Anything else out there? More than anything I just want to have hopefully a great conversation on this subject.

I'll add that im working as hard as ever in gym and kitchen but as we all know on ADT it's a war we're unarmed for....

Thanks all

[PCaWarrior]

Take it for what it's worth. Maybe I was just lucky. In 2018 I was diagnosed T3a G4+5 N1M0 stage 4 (T3a is on my pathology report but surgeon indicated T4 - both are bad). HSPC->CRPC progression SOC stats show that I had 1-2 years as HSPC. As of now I'm still HSPC. Odds are <1% that I would be HSPC if I followed the no-T SOC approach.

Clinical Timeline

07/2018:

• Diagnosed by biopsy

12/2018:

• Radical Prostatectomy:

• Pathology: Gleason 4+5=9, pT3b (seminal vesicle invasion, bladder neck involvement).

• Positive margins, 1/18 lymph nodes metastatic.

• Post-op PSA: <0.01 ng/mL.

5/2019–10/2019:

• ADT + Abiraterone: Testosterone <10 ng/dL, PSA <0.01 ng/mL.

11/2019–8/2021:

• Supraphysiologic Testosterone (SPT): Weekly testosterone cypionate (T >1,500 ng/dL).

• PSA rise to 0.17 ng/mL prompted therapy change.

9/2021–Present:

Treatment Protocol

pBAT:

• Testosterone Propionate: 50 mg intramuscular (IM) every 3 days during High-T phases.

• Androgen Deprivation Therapy (ADT): Continuous suppression of endogenous testosterone.

• Darolutamide (Nubeqa): Administered during Low-T phases with a 2-day washout pre-High-T.

Cycle Structure:

• Variable Cycle Length: 2–70 days, adjusted based on PSA kinetics and clinical response.

• PARP Inhibition: Olaparib (300 mg daily) added for 6 days/cycle (3 days pre-High-T to 3 days post-High-T) to exploit DNA repair vulnerability during androgen fluctuations.

Cyclic Adaptation

1. High-T Phase:

• Serum testosterone peaks at 1,500–2,000 ng/dL (Cmax at 24–48 hours post-injection).

• PSA Elevation: Rises to 1.5–3.0 ng/mL, reflecting AR-driven tumor stress.

2. Low-T Phase:

• Testosterone troughs at <20 ng/dL (2-day washout ensures clearance).

• PSA Decline: Drops to 0.4–0.6 ng/mL, indicating therapeutic response.

Mechanistic Rationale

• Testosterone Propionate: Short-acting ester induces rapid AR overload, triggering TOP2B-mediated DNA damage.

• Darolutamide: Blocks residual AR activity during Low-T, preventing adaptive resistance.

• Olaparib Timing: Targets BRCA/HRD-deficient clones during replication stress induced by testosterone fluctuations.

Therapeutic Outcomes

• PSA Dynamics: Cyclic PSA fluctuations (↑1.5–3.0 → ↓0.4–0.6 ng/mL) suggest ongoing tumor responsiveness without castration resistance.

• Safety Profile: No significant hematologic, hepatic, or cardiovascular adverse events reported.

Key Findings

1. Sustained HSPC status for 7 years.

2. Genomic Profiling (Tempus xT, 2019):

• Somatic Mutations:

• KMT2D truncating mutations (p.R4484*, p.S5147fs; VAF 13–22%).

• SYK/KDR splice variants (VAF 10–45%).

• Tumor Mutational Burden (TMB): 1.2 mut/Mb (16th percentile).

• MSI Status: Stable.

3. Circulating Tumor DNA (Guardant360, 2022–2023):

• 2022–2023 Serial Testing:

• TMB declined from 4.6 → 4.07 → 1.2 mut/Mb.

• ctDNA: Undetectable in all 4 tests (01/2022–09/2023).

4. Proteomics (OncoOmicsDx, 2023):

• AR Protein: 303 amol/μg (↑ vs. median 371 amol/μg).

• Resistance Markers:

• ERCC1/TUBB3: Undetectable (↓ platinum/taxane resistance).

• IGF1R: 177 amol/μg (↑ vs. median 268 amol/μg).

Mechanistic Rationale for pBAT Efficacy

1. Androgen Receptor (AR) Dynamics

• AR Overload: Supraphysiologic testosterone (T >1,500 ng/dL) induces AR signaling overload, triggering:

• TOP2B-mediated DNA damage via AR/TOP2B co-localization.

• Autophagic cell death in AR-dependent clones.

• pBAT Advantage: Testosterone propionate’s short half-life (19–48 hours) creates rapid T fluctuations, preventing adaptive AR splicing (e.g., AR-V7).

2. Epigenetic Modulation

• KMT2D Loss: Truncating mutations in KMT2D (histone methyltransferase) may sensitize cells to BAT-induced epigenetic stress by impairing DNA repair.

3. Immunogenic Pressure

• Low TMB/MSI Stability: Suggests neoantigen-poor tumor, reducing immunoediting risk.

• Heat Shock Protein (HSP) Activation: Chronic AR stress may upregulate HSP90/70, inhibiting pro-survival NF-κB pathways.

Clinical Implications

1. Unconventional HSPC Management

• Delayed Castration Resistance: 7-year HSPC duration defies typical progression timelines for G9/T3 disease.

• pBAT Synergy with ADT: Continuous AR axis disruption prevents clonal selection for CRPC phenotypes.

2. Biomarker-Driven Insights

• AR Protein Overexpression: Correlates with BAT responsiveness; AR 303 amol/μg exceeds 75th percentile in prostate cancer.

• Declining TMB: Mirrors reduced tumor heterogeneity under pBAT pressure.

3. Future Directions

• Combination Therapies:

• IGF1R inhibitors (e.g., xentuzumab) + pBAT for additive AR/IGF1R pathway blockade.

• PARP inhibitors (e.g., niraparib) targeting KMT2D-deficient homologous recombination.

• Clinical Trial Design:

• Phase II study of pBAT in high-risk.

Clinical Relevance:

• BAT has typically been used on CRPC men. TRANSFORMER and RESTORE are examples.

• A phase II BAT study (BATMAN) showed evidence that BAT can be applied to HSPC.

Research Impact:

• Supports BAT initiation during HSPC to delay castration resistance.

• Highlights KMT2D mutations as potential predictive biomarkers for stress-induced therapies.

Conclusion

This case demonstrates unprecedented HSPC control in G9/T3 prostate cancer using early pBAT, challenging traditional CRPC-focused BAT applications. Biomarker evolution (declining TMB, undetectable ctDNA) and AR/IGF1R proteomic profiles provide mechanistic insights into BAT’s efficacy in hormone-sensitive settings.

[PCaWarrior in reply to PCaWarrior]

References:

1. TRANSFORMER

Trial and results: clinicaltrials.gov/ct2/show...

Commentary: TRANSFORMER: A Randomized Phase II Study Comparing Bipolar Androgen Therapy Versus Enzalutamide in Asymptomatic Men With Castration-Resistant Metastatic Prostate Cancer – PMC ncbi.nlm.nih.gov/pmc/articl...

2. Olaparib + BAT

Trial and results: clinicaltrials.gov/ct2/show...

Summary: ESMO 2021: Bipolar Androgen Therapy (BAT) Plus Olaparib in Men With Metastatic Castration-Resistant Prostate Cancer urotoday.com/conference-hig...

Details: Clinical Study Protocol (CSP) cdn.clinicaltrials.gov/larg...

3. RESTORE

Trial and results: clinicaltrials.gov/ct2/show...

Summary: A Multicohort Open-label Phase II Trial of Bipolar Androgen Therapy in Men with Metastatic Castration-resistant Prostate Cancer (RESTORE): A Comparison of Post-abiraterone Versus Post-enzalutamide Cohorts ncbi.nlm.nih.gov/pmc/articl...

Commentary: A Multicohort Open-label Phase II Trial of Bipolar Androgen Therapy in Men with Metastatic Castration-resistant Prostate Cancer (RESTORE): A Comparison of Post-abiraterone Versus Post-enzalutamide Cohorts – PMC ncbi.nlm.nih.gov/pmc/articl...

4. BATMAN

Clinical trial clinicaltrials.gov/ct2/show...

PSA provocation by bipolar androgen therapy may predict duration of response to first-line androgen deprivation: Updated results from the BATMAN study – PubMed pubmed.ncbi.nlm.nih.gov/359...

PSA provocation by bipolar androgen therapy may predict duration of response to first‐line androgen deprivation: Updated results from the BATMAN study - Denmeade - 2022 - The Prostate - Wiley Online Library onlinelibrary.wiley.com/doi...

[Ichthus316 in reply to PCaWarrior]

Thanks for the update on your pBAT regimen. Why have you switched your Tp injections from eod to every 3rd day? Do you have new Cmax data that indicates a longer time to reach peak than previously thought?

And why is there such a big spread in the half-life (19-48 hrs)?

[PCaWarrior in reply to Ichthus316]

Thanks for pointing those errors out. Where did I specify the 3rd day? I need to fix that. And I'm going to tighten up the half-life. Those are numbers from various studies but the half-life I've observed in myself and others is 30-40 hours.

[Ichthus316 in reply to PCaWarrior]

In your first reply to this post, the 9th bullet point reads:• Testosterone Propionate: 50 mg intramuscular (IM) every 3 days during High-T phases.

[PCaWarrior in reply to Ichthus316]

Ok. I think I got it all.

Case Study: Long-Term Hormone-Sensitive Prostate Cancer (HSPC) Maintenance with Propionate-Based Bipolar Androgen Therapy (pBAT)

Authors: Dr. James Spurgeon ([e-mail]), Russ Hollyer ([e-mail])

Patient Profile: 62-year-old male with high-risk prostate cancer (Gleason 9, pT3bN1), diagnosed in 2018 at age 55.

Clinical Timeline

12/2018

• Radical Prostatectomy:

• Pathology: Gleason 4+5=9, pT3b (seminal vesicle invasion, bladder neck involvement).

• Positive margins, 1/18 lymph nodes metastatic.

• Post-op PSA: <0.01 ng/mL.

5/2019–10/2019

• ADT (tE2) + Abiraterone:

• Testosterone <10 ng/dL, PSA <0.01 ng/mL.

11/2019–8/2021

• Supraphysiologic Testosterone (SPT):

• Weekly testosterone cypionate (T >1,500 ng/dL).

• PSA rise to 0.17 ng/mL prompted therapy change.

9/2021–Present

• pBAT Protocol:

• Sustained HSPC status for 4+ years with cyclic PSA fluctuations (1.5–3.0 ng/mL on High-T, 0.4–0.6 ng/mL on Low-T).

Treatment Protocol

pBAT Regimen

1. Testosterone Propionate: 50 mg intramuscular (IM) every 2 days during High-T phases.

2. Testosterone Base (Aquaviron): 50 mg IM as needed for rapid peaks (Cmax ~1,500–2,000 ng/dL within 2–4 hours).

3. ADT: Continuous suppression of endogenous testosterone.

4. Darolutamide (Nubeqa): Administered during Low-T phases after a 2-day washout post-High-T.

5. Olaparib: 300 mg daily for 6 days/cycle (3 days pre- and post-High-T).

Cycle Structure

• Variable Duration: 2–70 days (adjusted via PSA kinetics).

• Rationale:

• Short cycles (2–7 days) for rapid response monitoring.

• Extended cycles (up to 70 days) to prolong suppression phases.

Key Findings

Biomarker Evolution

Parameter 2019 (Post-RP) 2022–2023 (pBAT)

TMB (mut/Mb) 1.2 4.6 → 1.2 → 0

ctDNA N/A Undetectable

AR Protein (amol/μg) N/A 303 (↓ vs. median 371)

IGF1R (amol/μg) N/A 177 (↓ vs. median 268)

Genomic Profiling (Tempus xT, 2019)

• Somatic Mutations:

• KMT2D truncating mutations (p.R4484*, p.S5147fs; VAF 13–22%).

• SYK/KDR splice variants (VAF 10–45%).

• TMB: 1.2 mut/Mb (16th percentile).

• MSI Status: Stable.

Mechanistic Rationale

1. Androgen Receptor (AR) Dynamics

• AR Overload: Supraphysiologic testosterone (T >1,500 ng/dL) induces AR signaling overload, triggering:

• TOP2B-mediated DNA damage via AR/TOP2B co-localization.

• Autophagic cell death in AR-dependent clones.

• pBAT Advantage: Testosterone propionate’s short half-life (30–40 hours) creates rapid T fluctuations, preventing adaptive AR splicing (e.g., AR-V7)1, 2

2. Epigenetic Modulation

• KMT2D Loss: Truncating mutations in KMT2D (histone methyltransferase) impair DNA repair, sensitizing cells to BAT-induced epigenetic stress3.

3. Immunogenic Pressure

• Low TMB/MSI Stability: Suggests neoantigen-poor tumor, reducing immunoediting risk.

• HSP Activation: Chronic AR stress upregulates HSP90/70, inhibiting pro-survival NF-κB pathways4.

Clinical Implications

1. Paradigm Challenge

• Delayed Castration Resistance: 7-year HSPC duration defies typical progression timelines for G9/T3 disease, supporting early BAT use in HSPC.

2. Biomarker-Driven Therapy

• Declining TMB/ctDNA: Suggests reduced tumor heterogeneity under pBAT pressure.

3. Future Directions

• Combination Therapies:

• IGF1R inhibitors (e.g., xentuzumab) + pBAT for additive pathway blockade.

• PARP inhibitors (e.g., talazoparib) targeting KMT2D-deficient homologous recombination.

• Clinical Trials: Phase II study of pBAT in high-risk HSPC (endpoints: CRPC-free survival, ctDNA clearance)5.

Safety and Tolerability

• Monitoring: Regular CBC, CMP, BP, Testosterone, and PSA tracking.

• Adverse Events: No significant hematologic (e.g., anemia), hepatic (e.g., elevated ALT/AST), or cardiovascular (e.g., hypertension) toxicity reported.

Conclusion

This case demonstrates unprecedented HSPC control in G9/T3 prostate cancer using early pBAT, challenging traditional CRPC-focused BAT applications. Biomarker evolution (declining TMB, undetectable ctDNA) and proteomic profiles provide mechanistic insights into BAT’s efficacy in hormone-sensitive settings.

References

1. Denmeade SR, et al. TRANSFORMER Trial. J Clin Oncol. 2021. [PMC8274807]

2. Markowski MC, et al. RESTORE Trial. Clin Cancer Res. 2021. [PMC7775877]

3. Denmeade SR, et al. BATMAN Study. The Prostate. 2022.[35938545]

4. Schweizer M, et al. Olaparib + BAT Trial. ESMO. 2021. [NCT03516812]

5. de Bono J, et al. Olaparib for Metastatic Castration-Resistant Prostate Cancer. N Engl J Med. 2020. [1911440]

[Ichthus316 in reply to PCaWarrior]

Thanks for this thorough info on your program and for letting us know what you find out about half-lives of the various kinds of T. Late this summer I may work in some rBAT cycles, so I will be integrating your latest thinking into the design.

[PCaWarrior in reply to Ichthus316]

Test Base supposedly has a very short half-life. Logical since it isn't esterized. I want to test it though. Aquaviron is the brand I'm going to test.

[PCaWarrior]

A quick note about SARMs or anabolics in general, we need to look carefully at the anabolic/androgenic ratio - simply, how anabolic are they (good part) vs how androgenic they are (usually the bad part).

Rad-140 has a 90:1 anabolic to androgenic ratio. That's super good.

Ostarine has a 10:1 ratio. Very good. But what makes it even a better choice is low binding for the ARs and it has some safety data.

I sometimes take a few mg/day of Ostarine or Rad.

It's a personal decision but I asked myself "what's the use of living 30 years if I look and feel like s..."? Answer for me was zero use. So I take little risks. I believe if we're smart about it the little risks can reward us with better health and also better PCa control.

[Yzinger]

Thanks for comments. I tend to agree on some risk. Educated and spoken to a doc of course too. I've mentioned before using sarms to my mo and at that time wasn't suggested. I didn't push issue as I trust my team but I do want to explore deeper

[PCaWarrior in reply to Yzinger]

I don't think many MOs will give their ok for SARMs. Liability. And they are right. There is a risk. They are not SOC and haven't been through extensive trials.

I will say (and say again and again and again...) that if I had followed SOC I'd probably be dead. SOC is good but I had really severe cancer and couldn't afford "good".

[Daveofnj]

Check out a book on BAT by Russ Hollyer available on Amazon for download.

[Yzinger]

I'll look for book. Hoping for more info on sarms as well.

[PCaWarrior in reply to Yzinger]

PM me and I'll send you a onedrive link to the latest one (much more info than the one on Amazon - plus it's completely free vs. the $2 that Amazon makes me charge).