Scary stuff

[PCaWarrior]

In the LNCaP-abl model, prolonged androgen deprivation across approximately 87 cell culture passages (roughly 8–12 months in vitro) drives prostate cancer cells to adapt to low-androgen conditions. This adaptation includes:

• AR Overexpression: A roughly 4-fold increase in androgen receptor (AR) protein levels.

• Androgen Hypersensitivity: The cells begin to proliferate in response to very low concentrations of synthetic androgen (0.001 nM versus 0.01 nM in the parental line).

Key Evidence from Studies:

• Passage 75: Cells develop a biphasic response—stimulation at low androgen levels and inhibition at high levels—which supports one of the concepts behind bipolar androgen therapy (BAT). Initiating pBAT early in hormone-sensitive prostate cancer (HSPC) may help prevent progression to castration-resistant prostate cancer (CRPC).

• Passage 87: AR transcriptional activity increases 30-fold compared to the parental cells.

Clinical Relevance:

In humans, similar resistance mechanisms—such as AR mutations (e.g., W741L)—can develop after 6–24 months of antiandrogen therapy. In typical HSPC cases, progression to CRPC usually takes 2–3 years in advanced prostate cancer, however this transition can occur as early as 6 months or as late as 6 years.

Darolutamide performs the best. Blocks more DHT and doesn't develop resistance as easily.

CRPC Progression:

• Typical: 1–3 years (median ~18 months) (1, 2).

• Aggressive Cases: ≤6 months (1, 2).

• Indolent Cases: Up to 6 years (2).

1. Identifying Patients With Rapid Progression From Hormone-Sensitive to Castration-Resistant Prostate Cancer: A Retrospective Study – PMC pmc.ncbi.nlm.nih.gov/articl...

2. Analysis of Risk Factors for Early Progression of Prostate Cancer After Initial Endocrine Therapy – PMC pmc.ncbi.nlm.nih.gov/articl...

Mateo, you're past 6 years; is that correct?

[Justfor_]

I am now 40 months and counting, but at a Minimum Effective Dosing, that, IMO, makes a hell of a difference. More is NOT better.

[PCaWarrior in reply to Justfor_]

My MO uses MED. I'm almost at 7 years. Still HSPC. G9 T3/4. PSA still low. Every time I get a PSA test done I hold my breath. I'm way over the statistics for a G9.

[petabyte in reply to Justfor_]

I was wondering what's the theory behind MED? And how is the dose determined?

[Justfor_ in reply to petabyte]

No theory needed, just follow the the time-tested wisdom: "Ουκ εν τω πολλώ το ευ" (more is not better). It has survived 25-26 centuries now. It can't be just rubbish.

How I adjust my dose:

healthunlocked.com/prostate...

[PCaWarrior in reply to petabyte]

Depends. Some is do it yourself. Some equivalency studies have been done. Moffit has done some of the work in this area.

[Ichthus316 in reply to petabyte]

If your question is about determining MED of ARSIs, I can offer a few thoughts about Nubeqa (darolutamide). I have been using it for the last 8 mos of each loT cycle of BAT. As PCaWarrior’s “scary” post illustrates, finding the MED is an important part of any therapy involving any ARSI because, logically, the lower (or less frequent) the dose, the longer the delay to resistance and disease progression if the dose is effective.

I’m unaware of any dose finding trials of darolutamide, but Bayer does allow a half dose (300 mg 2x/d) for certain conditions involving adverse reactions, renal/hepatic impairment, etc. Therefore, they must believe that a half dose is effective. They do NOT recommend dose reduction below 300 mg 2x/d, but don’t provide further details.

That leaves me to be the guinea pig for determining my own MED, which is risky. But developing resistance to daro & possible CRPC is a far greater risk, IMO. So I’m considering reducing the half dose I’m on now to 3/8 or 1/4 and monitoring the effect on PSA.

[KocoPr in reply to Ichthus316]

The thing is is we only do daro for two weeks before high T so i think i want to stick to full dose for now to just shut any chance of freeing the beast.

In contradiction to my statement above:

In my case at full dose after 1.5 yrs on pBAT 2wks on 1wk washout, 2 wks daro/orgo i eventually failed as my psa started rising on both cycles then i stayed on ADT cycle for a month then tried a 6 week high T cycle with cypionate and never made it to the full 6 weeks before i had a huge spike from 1.? To 6.? And picked up two bone mets. So needless to say i am on a longer ADT cycle till i bring my psa back to 0.05 which so far after 2 1/2 months im down to 0.25 and still going down.

[PCaWarrior in reply to KocoPr]

You both make good points. MED vs. full strength but limited time. Unfortunately, without trial or study data, we're guessing.

I use the averaging approach

Sometimes I use MDT, sometimes MED, sometimes nothing at all.

I'm trying to get a feel for Zytiga to see if I might be able to use it occasionally.