ASCO 2019 Abstracts.

[pjoshea13]

abstracts.asco.org/239/CatA...

Some interesting stuff.

As I was writing, Johann S. De Bono (presumably) was presenting abstract [1].

Here is a little background [2]:

"Resistance invariably develops to antiandrogen therapies used to treat newly diagnosed prostate cancers, but effective treatments for castration-resistant disease remain elusive. Here, we report that the transcriptional coactivator CBP/p300 is required to maintain the growth of castration-resistant prostate cancer."

-Patrick

[1] abstracts.asco.org/239/Abst...

Author(s): Johann S. De Bono, Elena Cojocaru, Elizabeth Ruth Plummer, Tomasz Knurowski, Karen Clegg, Fay Ashby, Neil Pegg, William West, Anthony Nigel Brooks; Royal Marsden NHS Foundation Trust and The Institute of Cancer Research, London, United Kingdom; Drug Development Unit-The Institute of Cancer Research and The Royal Marsden NHS Foundation Trust, Sutton, United Kingdom; Northern Centre for Cancer Care, Newcastle-upon-Tyne, United Kingdom; CellCentric Ltd, Cambridge, United Kingdom

Abstract Disclosures

Abstract:

Background: CCS1477 is a potent, selective and orally bioavailable inhibitor of the bromodomain of p300 and CBP, two homologous and critical co-activators of the androgen receptor (AR) and its variant forms, including mutated, amplified and spliced AR, as well as c-Myc. CCS1477 represents a new therapeutic option for prostate cancer patients who have progressed after failure of anti-androgen therapy and in combination with anti-androgens such as enzalutamide or abiraterone. Methods: This is a Ph I/IIa study to determine the maximum tolerated dose (MTD) and/or recommended Phase II dose and schedule(s) of CCS1477 and investigate clinical activity of CCS1477 monotherapy and CCS1477 in combination with abiraterone or enzalutamide in patients with metastatic castration resistant prostate cancer (mCRPC). The trial aims to enrol approximately 150 patients and is currently recruiting in the UK with plans to open additional sites in the USA (NCT03568656). Key inclusion criteria (for the mCRPC) require previous treatment with abiraterone and/or enzalutamide, taxane as well as evidence of disease progression (PCWG-3 guidelines). Single dose and steady state pharmacokinetics will be determined along with changes in plasma PSA, LDH and ALKP and in circulating tumour cell number. Anti-tumour activity will be determined by standard imaging according to PCWG-3 guidelines. Paired tumour biopsies for biomarker assessment are being collected. Cohort 1 of the monotherapy dose-escalation (rolling 6 design; 3-6 patients/cohort) has completed. Enrolment to cohort 2 began in January 2019. Dose finding in combination (CCS1477 + abiraterone; CCS1477 + enzalutamide) will be open once monotherapy dose escalation completes. Following definition of a recommended phase 2 dose and schedule for monotherapy and in combination, three expansion arms in patients with mCRPC will be opened in parallel (25 patients/arm); CCS1477 monotherapy; CCS1477 + abiraterone; CCS1477 + enzalutamide. A further expansion in patients with advanced solid tumours with a mutation in p300 or CBP will also be opened. Clinical trial information: NCT03568656

[2] cancerres.aacrjournals.org/...

[snoraste]

lots of good pieces -

[NPfisherman]

Thank you for posting this information....the science just keep marching...

Fish

[Hidden]

Hello Patrick,

Have not talked much with you lately, but always read your posts as religion.

Nice reads, thank you brother....

Cheers,

George

[GP24]

The company CellCentric in the UK produces the CCS1477 drug:

cellcentric.com/ccs1477/

[podsart]

Thanks, What do think of the article in this ASCO list?—

“ 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.”

[pjoshea13 in reply to podsart]

When I was diagnosed 15 years ago, I began a crash course on the PCa literature for hormones, vitamins, minerals, etc. PCa was a research backwater then, compared to today. Before the deluge I even kept paper files of important studies! LOL.

Something that left a big impression on me was that the androgen receptor [AR] was typically of the "wild type" at diagnosis, and that alterations were not due to normal disease progression, but rather, as an adaptation to ADT. The mantra at the time was that ADT failed within 18 to 24 months for most men. Not something that one likes to hear at age 56.

The idea that testosterone [T] might be reintroduced was not new. I believe that Huggins even discussed it. There is a 1967 paper: "Response of men with advanced prostatic carcinoma to exogenous administration of testosterone." (Prout & Brewer) [1]. & in 1981: "The response of metastatic adenocarcinoma of the prostate to exogenous testosterone." (Fowler & Whitmore) [2].

Some men respond to T restoration, but it was clear to me that ADT had to be delayed as long as possible. When is premature short-lived palliative treatment ever a good idea? Fortunately, I came across a hypothesis that T might be used to reset the clock. (I wish that I could remember the author's name.)

In 1995, Kallioniemi (Finland) reported that [3]:

"Overexpression of amplified genes is often associated with the acquisition of resistance to cancer therapeutic agents in vitro. We have identified a similar molecular mechanism in vivo for endocrine treatment failure in human prostate cancer which involves amplification of the androgen receptor (AR) gene. Comparative genomic hybridization shows that amplification of the Xq11-q13 region (the location), is common in tumours recurring during androgen deprivation therapy. We found high-level AR amplification in seven of 23 (30%) recurrent tumours, but in none of the specimens taken from the same patients prior to therapy. Our results suggest that AR amplification emerges during androgen deprivation therapy by facilitating tumour cell growth in low androgen concentrations."

No need to go into other common causes of treatment resistance, (or how Abiraterone & Enzalutamide have complicated the issue.) It seemed to me that when I eventually needed ADT, I should limit it to 3 months, say, & immediately reinstate T, for, say, another 3 months. Perhaps I could do better than 18-24 months with repeated ADT-T cycles?

When I first came across Denmeade's BAT concept, I was not enthralled. For 3 months out of 6, I had been experiencing a good QoL with high-normal T levels. With BAT, there is a monthly shot of T cypionate, but T itself is introduced merely to prolong ADT - perhaps indefinitely, but there is no real ADT vacation, as there is with intermittent ADT [IADT].

More recently, I questioned my use of 3-month on-off phases. Perhaps a more rapid cycle was better? I have now been on a BAT-like monthly cycle for 6 months.

In the new study:

"HDT {High-dose testosterone} was safe and active in a subset of mCRPC. ... Further understanding of the genomic alterations predicting responsiveness to HDT in mCRPC is required."

There isn't much new here, IMO.

I think it is extremely important for doctors to have useful options following castrate-resistance. However, I really think it is about time that CRPC ceased to be an inevitable treatment outcome.

-Patrick

[1] ncbi.nlm.nih.gov/pubmed/416...

[2] ncbi.nlm.nih.gov/pubmed/727...

[3] ncbi.nlm.nih.gov/pubmed/779...

[podsart]

Thanks, I appreciate your research and associated diligence. Helps me in my discussions with my onco

My case may provide a clue as my Supra T is a result of my Xtandi treatment without Lupron. Apparently, a fraction of those like me that Dr Myers put on this regimen have a Supra T response with associated benefits. I believe Friedman in his book discusses the importance of using bio indentical human T rather than the type they keep referring to in the study. Perhaps the endogenous Supra T response helps prevent AR mutation, which helps Xtandi last longer, which keeps T at Supra levels, and so on. Just a thought. Maybe using bio identical T might help. Friedman said can get it I think

[pjoshea13]

My experience with T now goes back 13 years:

- I began with androstenedione (andro). I laid in a supply before it was banned (in 2004), but didn't start using it immediately. I used chrysin to inhibit aromatization to estradiol.

- my integrative doc prefers supplements to drugs, but he is wary of chrysin & advised that I switch to Arimidex. When I ran out of andro, he prescribed Androderm (5 mg) patches. Company later lowered maximum dose to 4 mg.

- when Aetna Medicare warned that I would need to justify my use of T, I switched to injected T cypionate. Cheap enough that I didn't need insurance to pay - but it was really the very expensive patches that insurance objected to.

I like the T cypionate. I inject on the first of the month. I am currently (since last month) using 1 mg DES from the 8th through month-end.

-Patrick

[sammamish]

Patrick what was your benchmark for starting BAT?

[pjoshea13 in reply to sammamish]

I should perhaps have beaten my PSA down before starting BAT. Instead, it was 27. The number isn't important, but the end-of-month trend is.

Last month was my first using DES. With 1 mg daily, the trend is essentially - no change. I will do another month at 1 mg, starting on the 8th, but I may need to raise the dose if I am to see a significant downward movement.

The compounding pharmacy gave me 800 caps (the prescription was only for 180 for 3 months, with 3 refills), so I have flexibility.

(Importantly, I check my D-dimer for clot activity.)

Thus far, no sign of CRPC, so I am content.

(Without BAT, etc, my PSADT is about 3 months & has been for years.)

-Patrick

[sammamish]

Reason I ask is I am less than .o3 PSA. Been doing hormones from the start over a year ago. Am thinking it might make sense to do BAT now, and not wait for the inevitable switch. Sounds like you waited for a rising g PSA while Adt?

[pjoshea13 in reply to sammamish]

I was doing 3 months castrate & 3 months high T. The PSA took 3 months to bounce back to the starting point while on T. & 3 months to get close to zero while castrate.

Perhaps I could have continued for a long while on that cycle, but the BAT cycle makes more sense to me. It's as rapid as one can get. How can cells adapt to low T when the body is flooded with T in a few weeks?

With BAT, of course, The PSA has less than a month to go down. In my old cycle, I was knocking it down close to zero. That might be a concern to someone starting with a high PSA.

In your case, PSA is irrelevant at this time. i.e. you wouldn't need to do as many tests as I have been doing.

I like oral DES for BAT, since I get a 7-day holiday each month. Denmeade's BAT uses continuous Lupron, etc. Also, DES has anti-PCa activity. The big objection is blood clots. That is a problem for everyone with PCa, regardless of treatment. With nattokinase (with or without low-dose aspirin) & D-dimer testing, clotting ceases to be an issue, IMO. But I have nothing against 'traditional' BAT.

-Patrick

[sammamish in reply to pjoshea13]

So what prompted you to initiate the therapy? Was it a rising PSA while on adr?

[pjoshea13 in reply to sammamish]

No, I was coming up to my 15-year PCa anniversary & reviewing how I might improve my chances of getting to 20 years.

Basically, I changed on a whim.

Who knows - my 3-month on/off cycle might be non-inferior? It certainly feels good to have high-normal T for 3 months at a time.

-Patrick

[sammamish]

So were you on adt long before starting adt/T therPy?

[pjoshea13 in reply to sammamish]

I have never been on conventional ADT.

I began using androstenedione, & then T, about 13 years ago. That was good for a while, but eventually I needed to periodically know PSA back down. I have never been castrate for more than 3 months, & T was always quickly restored to ~1,000 ng/dL.

-P.

[pjoshea13 in reply to pjoshea13]

should read: "periodically knock PSA back down"