more possibilities after exhausting SOC?: Enzalutamide-resistant castration-resistant prostate cancer: challenges and solutions

[JLS1]

Onco Targets Ther. 2018; 11: 7353–7368.

Published online 2018 Oct 24. doi: 10.2147/OTT.S153764

PMCID: PMC6204864

PMID: 30425524

Enzalutamide-resistant castration-resistant prostate cancer: challenges and solutions

ncbi.nlm.nih.gov/pmc/articl...

"AR amplification and overexpression

Up to 80% of CRPC patients show AR protein overexpression, and in 20%–30% of patients, this is related to AR gene amplification.23 In vitro studies demonstrate that this alteration is more frequent in patients progressing on enzalutamide than in treatment-naïve patients,24 and consequently, it is considered as a potential mechanism of resistance. In a cohort of patients previously treated with either enzalutamide or orteronel, a CYP17A inhibitor, 50% showed the evidence of AR amplification and only 13% had a clinically significant response when treated with abiraterone.24,25 These observations have been confirmed in a correlative biomarker study, in a cohort of 94 patients treated with enzalutamide in the context of the PREMIERE trial; AR-amplified tumors had a poor response to treatment and a largely shorter OS (HR 11.08, 95% CI 2.16–56.95, P<0.004).26

A promising strategy to block AR overexpression consists in the administration of supraphysiologic doses of testosterone, that in the preclinical models prevented PC cell growth.27,28 Unfortunately, this effect vanishes away in a short time, and PC cells progressively downregulate the AR, restoring cell growth in the presence of testosterone. A potential viable therapeutic approach consists in the so-called “bipolar androgen therapy”, namely the swinging from supraphysiologic levels of androgens to near-castrate levels. The results of a Phase II trial testing this strategy in mCRPC patients after progression on enzalutamide have been recently published.29 Nine of the 30 enrolled patients (30%; 95% CI 15%–49%) achieved a .50% PSA reduction, and 21 proceeded to enzalutamide rechallenge, with 15 patients (52%; 95% CI 33%–71%) experiencing .50% PSA reduction.29 Two Phase II trials are currently recruiting patients: the first (NCT02286921) aims to confirm the therapeutic benefits of the bipolar androgen therapy, while the second (NCT02090114) is designed to test the activity and efficacy of sustained supraphysiologic testosterone concentration (Table 1)."

[JLS1]

Thank you!

[kaptank]

There has been quite a bit of discussion and reporting on BAT here and at least some of us have done it including me. The search bar will bring up lots. I think BAT is useful to extend the use of the antiandrogens. Some use it from the start to prevent resistance, others to reverse resistance when it happens. Eventually (but this may be enough) it fails, as do all other approaches to this adaptive monster. It's a management tool.

The second trial, Continuous HighT (CHT) is interesting because there is no reliable data on this and the in vitro work indicates it may be more effective than BAT. I tried it in the midst of my BAT experiment by injecting 200mg T cypionate ever 2nd day after the initial 400mg. Well and truly supraphysiologic. I did this for 2 weeks and stopped due to lack of nerve. I concluded no short term difference to BAT, which extended longterm use of bicalutamide (an older antiandrogen) from 1 to 3 years.

[cesanon in reply to kaptank]

Sartor at Tulane is a believer in Continuous HighT (CHT)

[podsart in reply to cesanon]

Any links to continuous supra T trials?

[cesces in reply to podsart]

I don't think they exist.

[podsart in reply to cesces]

Ok thanks

[cesces in reply to podsart]

If you are interested. I would schedule an appointment with Sartor at Tulane.

He is a pretty open thinker. He might come up with additional options as well.

[kaptank in reply to cesanon]

There are anecdotal reports of use of High T going back to the 1980s (mostly involving US Drs) but results are mixed and it is unclear whether they used truly supraphysiological levels rather than high but still within physiological levels. Generally patches will not get you to supra T levels (but there is great individual variability). Intramuscular injection required. By supraT I mean at least twice the max physiological level. A review by Mahomad et al ( ref in some of my previous posts) found the only reports of unambiguously supraT were those of Denmeade/Johns Hopkins using BAT. Mahommad speculated that whether continuous supraT works will depend on which pathway (among many) supraT works. eg double strand DNA breaks vs downregulation of androgen receptor variants.

[cesces in reply to kaptank]

I recollect that Tall Allen has said that bipolar therapy only works about half the time.

It might make sense to start with Bipolar first to see if your psa goes up or down with the initial treatment.

[kaptank in reply to cesces]

I agree- we know more about BAT. There are 2 effects: response (PSA) to supraT, and resensitising previous failed antiandrogen. The second is more important and can happen even if the first fails.

[cesces in reply to kaptank]

You mean you can generate an increased psa while concurrently resensitising to previous failed antiandrogen?

????!!!

[kaptank in reply to cesces]

Yes. When I repeated BAT I had modest increases in PSA during the BAT phase but a 50% reduction on rechallenge.

[cesces in reply to kaptank]

Wow.

What Doc supervised your treatment?

[kaptank in reply to cesces]

None.

[Currumpaw]

Hey JLS1!

Just mentioning that Dr. Laurence Klotz recently was involved with and posted a study using capsaicin for prostate cancer.

He became interested when one of his patients who was hormone resistant stabilized his PSA by dosing himself with ho sauce.

You might look into it.

Currumpaw