high dose testosterone and androgen receptors

[kaptank]

Below is the abstract for a poster at the forthcoming ASCO meeting. They followed 33 mcrPca patients whose androgen blocking therapy had failed and looked at changes in DNA and androgen receptor expressions under a high dose testosterone regime - both BAT style and continuous gel. Interestingly, they had patients with bone mets. High T decreased altered AR expression in 100% of patients that had altered ARs at the start. Both BAT and gel were effective and the overall result seems to indicate that resensitization to androgen blockers is possible. Small sample, no longer term follow up but interesting.

abstracts.asco.org/239/Abst...

"AR changes in circulating-tumor DNA (ctDNA) in patients with metastatic castration-resistant prostate cancer (mCRPC) treated with high-dose testosterone.

Sub-category:

Advanced Disease

Category:

Genitourinary (Prostate) Cancer

Meeting:

2019 ASCO Annual Meeting

Abstract No:

5058

Poster Board Number:

Poster Session (Board #170)

Citation:

J Clin Oncol 37, 2019 (suppl; abstr 5058)

Author(s): Marcus W. Moses, Elisa Ledet, Charlotte Manogue, Patrick Cotogno, Brian E. Lewis, A. Oliver Sartor, Pedro C. Barata, Jodi Lyn Layton; Tulane University, New Orleans, LA; Tulane University Cancer Center, New Orleans, LA; Office of Clinical Research, Tulane Cancer Center, New Orleans, LA; Tulane University School of Medicine, New Orleans, LA; Tulane Medical School, New Orleans, LA

Abstract Disclosures

Abstract:

Background: High-dose testosterone (HDT) is active in mCRPC pts and may allow successful re-sensitization to previously utilized androgen-axis targeted therapies. The relationship of genomic alterations in AR gene to HDT responsiveness is unclear. Methods: Analysis of consecutive pts treated with ≥1 dose of HDT (testosterone cypionate q 2-4 weeks n = 29; continuous gel n = 4). Baseline characteristics, ctDNA data (Guardant360), and clinical outcomes were assessed. Presence of genomic AR alterations included amplifications (amps) and mutations (muts); all muts had allele fraction ≥0.3%. PSA response rates included PSA declines of > 30% or ≥50%. PSA-progression-free survival (PSA-PFS) was defined as HDT start date to PSA ≥ 25% over baseline after a second confirmed PSA rise. Results: Between May 2016 and Feb 2018, 33 mCRPC pts had median age 73 (58-85), 39% Gleason 8-10, 100% bone mets, 24% nodes + bone, and median baseline PSA level 36.1 ng/mL (0.04-1290). HDT was given post-median of 2 (1-10) CRPC therapies. 73% (24/33) of pts previously received abiraterone (n = 14), enzalutamide (n = 4), or both sequentially (n = 6) prior to HDT for a median of 10.5 months (0.7-56.8). Baseline ctDNA showed 42% AR alterations (amps = 8, muts = 4, both = 2); 33% TP53, and 6% DNA repair (ATM n = 1; BRCA2 n = 1). With median follow-up 4.4 months, HDT given for median of 4.2 months (95% CI, 3.6-4.8); 29% had PSA ≥50% response and 45% PSA ≥30% response. Median PSA-PFS is immature at 5.5 months (95% CI, 1.5-9.5); 14 pts still on HDT treatment. Grade ≥3 AEs were observed in 6% of pts (G4 thrombocytopenia = 1; G4 asthenia = 1). For pts with baseline AR alterations and HDT treatment, repeated ctDNA assays (n = 7) showed that 100% had decreased AR alterations. No relationship between PSA response and baseline ctDNA AR characteristics are discerned at this time. Conclusions: HDT was safe and active in a subset of mCRPC. Responses were clearly noted for men receiving continuous daily testosterone gels, thus continuously high testosterone levels are active in addition to injection-induced bipolar changes. Further understanding of the genomic alterations predicting responsiveness to HDT in mCRPC is required."

[FCoffey]

Interesting, I would like to see the whole paper, which doesn't always happen with ASCO posters.

They found that 100% of men with AR receptor mutations when the study started showed reduced alterations after high dose testosterone therapy, but that did not translate into predicting whether their PSA would go down substantially.

Hopefully it does mean that those men are re-sensitized to ADT+abiraterone or enzalutamide.

Interesting also that keeping testosterone continuously elevated seems to work, the rapid cycling of BAT may not be necessary, at least not in all patients.

[Fairwind]

It's very difficult to get any solid trials and studies on a simple treatment that uses a dirt-cheap generic drug (Testosterone)..The "system" almost forces you to try the D.I.Y. route and hope for the best..

[kaptank in reply to Fairwind]

Very true. However the evidence is mounting from these small phase 2 type trials confirming that something interesting is happening regarding resensitization. In the US it seems there are some oncos and general practitioners willing to give it a try. Here in Australia no one but nobody will prescribe T to PCa patients because there is a general fear of litigation if medicos step outside SOC and government campaigns against steroid abuse - any such prescription will draw the attention of authorities. I think in due course high T will become a standard tool of management as we learn more about it. But not yet.

[Hidden]

was a high dose testosterone ever tried for castrate sensitive patients instead of ADT?

[kaptank in reply to Hidden]

I don't know, it would be a brave patient that went to continuous HDT before ADT. (ie, HDT as first line treatment) There are major gaps in our knowledge of T and PCa, mainly due to the false assumption that "T is fuel for cancer". However there are correspondents here who do BAT with ADT with the aim of warding off resistance to ADT with some success.