Are you currently (or have you been) in a Clinical Trial?
Comments
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Clinical studies do have the ability to examine all of those data, and the FDA would require such before approving. No way will they let a new med out if data show it cures 2 out of 10 but leads to the death of the other 8. The initial data look compelling enough that I really want my wife to participate in the next round of studies. But as you know, there are always so many exclusion criteria that she may not qualify. With that said...enobosarm is readily available in the grey/black market body building circles...it is just a matter of finding a reliable and quality controlled source (which, sadly, I have no clue how to do).
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hi all,
I'm starting tomivosertib and paclitaxel, NCT04261218 on Tuesday after liver biopsy and labs on Monday. Anyone else? I connected with one other person who has been on the trial for a couple of months, but otherwise I have heard or read nothing about it. I'm a bit scared and a lot hopeful.
cheers, dee
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Cure-ious:Does ones PR status matter as far as how Enobosarm works? The articles only mentio ER or HER status. What if one is single hormone positive?
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Elenas, I haven't seen any mention that PR status matters. Androgen receptor (AR) is expressed in 80%–95% of ER-positive breast cancers, and Enobosarm stimulates AR to inhibit ER. Both luminal A and B MBCs have been shown to respond, and luminal B often have low PR expression, which suggests PR expression is not required. Moreover, mutant ERs that appear during resistance to endocrine therapy also respond well to Enobosarm, so at least some endocrine-resistant cancers are inhibited by the drug. Enobosarm has also been in clinical trial to treat cachexia (muscle loss and wasting) in advanced cancers.
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good luck on your trial gg27. Keep us in the loop how you are doing. Dee
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Hi GG27 - I am not familiar with the trial. Sending your way lots of good response to treatment vibes. ~Kar
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https://medicalxpress.com/news/2021-05-lasofoxifene-treatment-resistant-breast-cancer.html. - but I believe you must have ESR1....
Also...Cureious...with reference to Enobosarm.... am I correct in seeing it hasn't even gone to trials yet? So that could take years to actually be able to get this drug right?
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Hey, Nicole- Lasofoxifene is great for normal or ESR1 mutant estrogen receptor, its just that Faslodex doesn't work well on some of the ESR1 mutations. So keep Lasofoxifene on the list.
Enobosarm had just completed a trial, I don't think there is anything open yet but the next one is supposed to be phase 3, and coming sometime in the second half of 2021. Same thing for ARV-471, next trial not expected until 2Q 2021. It will be interesting to compare the details of these two trials; it is possible that neither of them will allow prior chemo treatment, because they are gunning for second or thirdline against faslodex and need to have good numbers.
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Not sure if this writeup about enobosarm has been posted or not yet:
Enobosarm Induces a 50% CBR in AR+/ER+ Metastatic Breast Cancer That Has Progressed on Palbociclib
May 17, 2021
Enobosarm has been shown to induce a clinical benefit rate of 50% at 24 weeks in evaluable patients with measurable metastatic androgren receptor–positive, estrogen receptor–positive, metastatic breast cancer that has progressed on treatment with palbociclib.
Carlo Palmieri, BSc, MBBS, PhD, FRCP
The nonsteroidal selective androgen receptor (AR) agonist enobosarm has been shown to induce a clinical benefit rate (CBR) of 50% at 24 weeks in evaluable patients with measurable metastatic AR-positive, estrogen receptor (ER)–positive, metastatic breast cancer that has progressed on treatment with the CDK4/6 inhibitor palbociclib (Ibrance), according to data from a phase 2 G200802 trial.1
Results presented during the ESMO Breast Virtual Congress 2021showed that the CBR at 24 weeks in evaluable patients who received the 9-mg dose of the agent (n = 50) was 32% (95% CI, 19.5%-46.7%) vs 29% (95% CI, 17.1%-43.1%) in those who received the 18-mg dose of the agent (n = 52). The median radiographic progression-free survival (rPFS) in the 9- and 18-mg cohorts was greater than 5.6 months (range, 0-27.5) and 4.2 months (range, 0-16.5), respectively.
Moreover, the best objective tumor response (BOR) in patients who had progressed on endocrine therapy and a CDK4/6 inhibitor in the metastatic setting was 30%, and this included 2 complete responses (CRs) and 1 partial response (PR). The overall mean rPFS was 10.0 months in those who received the agent at a dose of 9 mg; in the 9-mg and 18-mg cohorts combined, the mean rPFS was 7.3 months.
Among 34 patients with measurable disease at baseline in the 9-mg cohort, the BOR per central read and RECIST v1.1 criteria, at any time during the study, was 29.4% (n = 10); this included a CR rate of 5.9% (n = 2) and a PR rate of 23.5% (n = 8). In 37 patients with measurable disease at baseline in the 18-mg cohort, the ORR was 24.3% (n = 9), with an 8.1% CR rate (n = 3) and a 16.2% PR rate (n = 6).
Androgens have historically been utilized in the treatment of patients with breast cancer; however, their virilizing effects have limited their clinical application in this population. In patients with ER-positive disease, AR agonists have been shown to hinder tumor growth. The majority of breast cancers, 70% to 95%, have AR positivity. Moreover, a high concordance rate of 70% has been observed between AR positivity in primary and metastatic lesions.
"AR positivity is an independent predictor of beneficial breast cancer outcome," lead study author Carlo Palmieri, BSc, MBBS, PhD, FRCP, of The Clatterbridge Cancer Center NHS Foundation Trust, and colleagues, wrote in a poster on the data. "The development of novel strategies to target the AR as a treatment for women with ER-positive breast cancer that have exhausted drugs that target the ER is warranted."
Enobosarm was developed to have selectivity for AR without cross-reactivity or binding to other steroidal hormone receptors. Because it is not a substrate for aromatase, the agent cannot be aromatized to estrogen. The agent was designed to build and heal bone and it possesses the potential to treat patients with antiestrogen-induced osteoporosis and help to prevent skeletal-related effects.
Previously, enobosarm has been shown to inhibit AR-positive/ER-positive breast cancer in cell and patient-derived xenograft models of endocrine-sensitive and -resistant disease, according to the study investigators.
Specifically, single-agent enobosarm was found to have greater inhibition of breast cancer that was resistant to an ER-targeting agent vs a CDK4/6 inhibitor in preclinical models. Moreover, when combined with a CDK4/6 inhibitor, the agent was found to have stronger inhibition of ER-targeting agent–resistant breast cancer vs either drug alone. In breast cancer cells that were resistant to both CDK4/6 inhibition and an ER-targeting agent, enobosarm was found to suppress breast cancer cells.
When paired with a CDK4/6 inhibitor, enobosarm further suppressed breast cancer cells that were resistant to both CDK4/6 inhibition and an ER-targeting agent; in fact, enobosarm was found to restore sensitivity to CDK4/6 inhibitors.
In the open-label, multicenter, parallel-design phase 2 G200802 trial, investigators set out to examine the safety and efficacy of oral enobosarm at a daily dose of either 9 mg (n = 72) or 18 mg (n = 64) in postmenopausal patients with AR-positive, ER-positive metastatic breast cancer.
To be eligible for enrollment, patients had to have metastatic or locally recurrent disease that was not amenable to surgery and they needed to have previously responded to adjuvant endocrine treatment for at least 3 years or more endocrine treatment for metastatic disease for 6 months or longer. The primary end point of the trial was CBR at 6 months via RECIST v1.1 criteria and biomarkers were also evaluated, including serum prostate-specific antigen and circulating tumor cells.
Baseline characteristics proved to be comparable between the 2 treatment cohorts.2 The median age of study participants in the 9-mg cohort was 60.5 years, while it was 62.5 years in the 18-mg cohort. More than half of the patients had an ECOG performance status of 0; this was true for 60.0% of those in the 9-mg arm and 53.8% of those in the 18-mg arm. Moreover, most patients in the 9- and 18-mg cohorts had previously received chemotherapy (90.0% and 92.3%, respectively). The median prior lines of endocrine therapy received was 3.2 (range, 1-7) in both treatment arms.
Additionally, EuroQoL-visual analogue scale (EQ-VAS) scores were obtained at baseline and during the study, at week 24 and end of therapy (EOT). For the entire instrument, a 8.6 (14.69; P = .002) improvement from baseline to EOT was observed in the 9-mg cohort vs 7.3 (16.67; P = .011) in the 18-mg cohort.
Specifically, in the 9- and 18-mg cohorts, the percentage of patients who experienced an improvement at week 24 in terms of mobility was 40% vs 50%, respectively; these rates were 50% and 29%, respectively, in terms of anxiety and depression and 50% and 31%, respectively, with regard to pain and discomfort.
Enobosarm was also found to be well tolerated, with most of the adverse effects (AEs) being just grade 1 or 2. Grade 3 treatment-related AEs (TRAEs) were reported by 5 patients in the 9-mg cohort (n = 75) and 9 patients in the 18-mg cohort (n = 61); 1 patient in each cohort experienced a grade 4 TRAE. However, no patients on either arm experienced a treatment-emergent AE that resulted in death.
The most frequently reported grade 3 or 4 TRAEs in the 9-mg cohort included increased aspartate aminotransferase (2.7%), hypercalcemia (2.6%), increased alanine aminotransferase (ALT; 1.3%), headache (1.3%), anemia (1.3%), and decreased appetite (1.3%). In the 18-mg cohort, the most commonly experienced grade 3 or 4 TRAEs comprised increased ALT (3.3%), hypercalcemia (3.3%), fatigue (3.3%), and tumor flare (3.3%).
In the phase 3 ARTEST trial, investigators are examining the safety and efficacy of enobosarm compared with exemestane or tamoxifen in the treatment of patients with metastatic, AR-positive/ER-positive/HER2-negative breast cancer who have progressed following treatment with a nonsteroidal aromatase inhibitor, fulvestrant, and a CDK4/6 inhibitor.
References
- Palmieri C, Linden H, Birrell S, et al. Phase 2 clinical study: efficacy of enobosarm, a selective androgen receptor (AR) targeting agent, in patients with metastatic AR+/ER+ advanced breast cancer resistant to estrogen receptor targeted agents and CDK 4/6 inhibitor in a phase 2 clinical study. Presented at: 2021 ESMO Breast Virtual Congress; May 5-8, 2021; Virtual. Poster 100P.
- Palmieri C, Linden H, Birrel S, et al. Efficacy and safety of enobosarm, a selective androgen receptor agonist, to target AR in women with advanced AR+/ER+ breast cancer– final results from an international Phase 2 randomized study (G200802). Presented at: 2020 San Antonio Breast Cancer Symposium; December 4-8, 2020; virtual. Abstract PD8-10.
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ASCO 2021 (June 4-8) Abstracts are available now:
https://meetinglibrary.asco.org/results?meetingVie...
Results of AMEERA-1 trial of the SERD Amcenestrant w/Ibrance (as of Feb.8). Prior chemo was allowed as well as one prior CDK4,6 inhibitor:
In pts with ER+/HER2– mBC, safety at the RP2D of amcenestrant + palbo was favorable, with no safety signals of bradycardia or eye disorders. Preliminary antitumor activity was observed (ORR: 31.4% and CBR: 74.3%). ORR (shrinking), CBR (stable for 6 month) are exciting numbers. Clinical trial information: NCT03284957.
The Phase 3 trial AMEERA-5 is testing this SERD with Ibrance in first-line treatment. This drug is one of a handful fighting to be the first to finally cross the finish line and apply for FDA approval, its been a long run for the SERDs and these are like 3rd or more generation versions
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Several years ago there were some AR-positive mbc patients trying the anti-androgen (androgen antagonist) drug enzalutamide (Xtandi) off label. (Approved for prostate cancer.) Now it appears this anti-androgen approach was the opposite of what should have been done, since we are seeing success with enobosarm, which is an androgen agonist. Promoting the androgen inhibits the ER pathway. Have I got that right?
I'll keep that drug in my pocket. Also we should have a big party when an oral SERD finally gets approved!
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It seems like for hormone receptor positive breast cancer, changes in hormone levels disrupt the cancer. Both blocking estrogen and adding estrogen have been employed successfully in the past. Obviously blocking has won out and that's why we see AI's and SERM and now SERD as standard treatment. An alternation between one after failure, often activates the other. It's possible that both introducing androgen and blocking androgens could both work, depending on the sequence of prior events.
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So how exactly do we know if we are AR+ or AR-??
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Although it looks like the odds are that most breast cancers are AR+, ultimately you would have to have a biopsy tested. It's probably not standard procedure as the significance just wasn't there previously. The testing for AR+ might be the same as used for prostate cancer, so it might be doable at any standard lab.
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SP, You got it right! As I recall, Hope (who started the Ibrance thread) chose the AR blocker as her last-shot clinical trial. She was right in her enthusiasm that the AR was a great target, but science was wrong at that time, and in principle Xtandi could have made the cancer even worse- a paper came out in Nat Comm last Nov showing definitively that AR is a tumor suppressor for ER-positive tumors, so you want to increase its activity, and that provides a whole different way to shut down ER activity.
If the cancer is ER-negative but AR-positive, they still use Xtandi to shut off AR- no benefit to increase AR activity in those tumors because there is no ER to shut down.
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Cure-ious: Are you sure that an ER negative cancer would not respond to an AR agonist?
That would make it clear that an ER negative patient should not take enobosarm, right?
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curious what about people like me ER+ PR- ??? Would the Enobosarm make it worse?
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Cure-ious, yes, when I asked that question I was thinking of Hope, who had ER+ AR+ ILC, and how her last treatment was the anti-androgen Xtandi. Sigh. Sometimes something seems to make sense, but further scientific investigation yields surprising results.
Here is an article describing different subtypes of triple negative (ER- PR- Her2-) breast cancer. Basal-like type 1 responds well to chemotherapy; basal-like type 2 is likely to respond to immunotherapy; and the AR-positive luminal type appears to respond to anti-androgen therapy. This word "luminal" is the same word used to describe many ER/PR positive breast cancers that are hormone-driven (at least at first). So perhaps this third type uses AR to grow. They are testing anti-androgen drugs for this type, I assume Xtandi or similar.
https://www.bcrf.org/blog/emerging-therapies-triple-negative-breast-cancer
About testing for AR -- The pathology report for the last breast biopsy I had (2014) reported on AR along with the standard ER, PR, Her2, etc. The AR test might have been ordered just for me but I suspect it is now standard at my cancer center.
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SP you mean the biopsy not F1 right?
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Yes, that's right.
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Husband11...I am guessing that I am like you, a husband doing his best to help his bride fight MBC. After failing AIs, Ibrance, and Everolimus, mine is currently much better post tomotherapy and taking a quasi-small dose of Xeloda. But her tumor is definitely AR+.
Enobosarm is quite intriguing as it seems so much less likely to cause adverse events than most other treatments. I spoke to our Onc at Mayo yesterday and she seemed completely unaware of it. I also spoke to a research Onc I've gotten to know, and they don't think they will be one of the study sites.
What is also interesting about enobosarm, is that it has been around for quite some time in the body building circles. It is decidedly a grey market area, but if push comes to shove, it appears as though one can get it online. I am not ready to go down that path at this point...but I wouldn't rule it out down the road,
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well apparently my tumor was low AR+.
(thanks husband, SP and Cureious I would be lost without yall)...according to this biopsy from 2 years ago..so I am still not sure if the Enobosarm would be good or bad for me?? Figures I can't just get something easy it has to be "maybe?...
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Husband, The lab experiments showed no benefit of enobosarm on cells lines that were ER-negative. I think they also deleted ER from a responsive cell type and showed that Enobosarm no longer works, confirming that ER is the ultimate target, indirect though the path may be. However, I thought I saw an older trial testing it on TNBC? If so, I don't know how that came out but the lab studies would say, nah, not going to work.This could be a case where science had it doubly wrong- setting up trials testing AR inhibitors on ER-positive cancers and AR-boosters on ER-negative; arrgh, such a waste! Anyway, the company is marketing Enobosarm as an anti-estrogen, like the SERDs.
Nicole, The ER is juat as active in cells lacking PR, so long as the cell also has AR, it should work.
SP, thanks for the info, AR levels can be very high in lobular cancers, finally a drug that helps!
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Curious...yes...about it being just as active in cells lacking PR, so long as the cell also has AR it should work...but my AR looks Low...so I was feeling like it would be more of a risk of it working the opposite way (promoting tumor growth)...either way I think I need a new biopsy...so when a new one grows in soft tissue I will definitely be getting one.
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Spouse - interesting post on enobosarm. I am 10% ? AR 80+% ER. ONcologist said a lot of effort/research going into AR, but nothing there yet. Your post and this site https://verupharma.com/pipeline/enobosarm/ suggests that there is. Is it avaiable through Rx or is it an unapproved drug?
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you can buy it on line...look up SARMS
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Certainly not approved. But Veru Pharma is looking to get the approval. In the meantime, it is available online via grey market "research" which seems to be used by bodybuilders and anti-aging folks. The question (for which I have no answer) is which of the online sites are reliable? I fear there are many enobosarm products that contain various other steroids and such.
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Nicole, I was just reading that ER-positive, PR-negative cancers are more likely than the ER/PR-positive cancers to mutate to express higher levels of HER2 protein and/or increased HER2 kinase activity leading to progression on endocrine therapy. These HER2-low cancers can then be treated with endocrine therapy plus neratinib or Enhertu, etc.
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Some of the sellers of ostarine / enobosarm claim to have third party testing of their product, and some regularly post recent testing results, science bio and chemyo are a couple that have a good reputation, but of course nothing beats FDA approved and purchased through a pharmacy, which isnt yet a reality. Science bio is getting out of the sarms business however. They do currently have stock of enobosarm
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What i would be interested in knowing is whether on an ER+, AR+ (even weakly AR+) breast cancer, is whether adding enobosarm would at worst have no effect on the cancer. It clearly has prospect of improving quality of life of patients, so if at worst all it did was strengthen the patient, improve mood, etc, that would be a win, if t turned out not to actually suppress the cancer. IE, a no lose gamble
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