ESR1 mutation treatment options and new SERD/SERM research

Mika- Some options for your list.

First, the Lasofoxifene trial is just about to add an arm C to their phase 1/2 trial, which will combine Lasofoxifene with Ibrance. Being off of CDk4,6 inhibitors for awhile you might respond better to the combo.

The trial Dee is on uses a PROTEAC (ARV-471) to degrade the estrogen receptor, and these are people who progressed on I/F - plus one woman who responded had also been previously on two different SERD trials!

Hi Karen! It's not totally unexpected because one particular mutation that is fairly common in ESR1 is known to be resistant to Faslodex - it is called Y537S. So there is the Lasofoxifene trial, about to add an arm where it is combined with Ibrance. Lasofoxifene is related to tamoxifen, and it binds and inhibits the activity of the mutant ESR1. It was fast-tracked by FDA in May 2019. A phase 2 trial combining it with physician choice is supposed to start this summer. Good news with this drug is that side effects are positive on bone, etc, unlike AIs

Then, Dee is taking ARV-471; she has it as monotherapy. A phase two trial for second or thirdline only will start in the summer, I think they will exclude prior IV-chemo in metastatic setting (would mean prior Xeloda is OK).

Then also you could try the Androgen Receptor booster drug Enobosarm. Its a totally different way to down-regulate ER signaling, so the cancer will not be resistant to it, and so long as the cancer remains estrogen-dependent then its a great choice. Again, the side effects are positive for muscle and bone building.

The PARP inhibitors are excellent drugs but they can work well also in later lines, usually they try to do the anti-hormone stuff first?

Karen I will post links to the specific trials you could consider so you can bring those along to show your MO..Where lasofoxifene is being marketed specifically for ESR1, the other two drugs are effective for either normal or ESR1 mutant cancers that have become resistant to AI and CDK4,6 inhibitor

Lasofoxifene (this trial is at Duke):

https://clinicaltrials.gov/ct2/show/NCT03781063

ARV-471 (this trial will open an arm this month to combine with Ibrance, a phase 2 trial is planned for this summer in various combos, for 2nd or 3rd line only):

https://clinicaltrials.gov/ct2/show/NCT04072952

https://ir.arvinas.com/news-releases/news-release-...

Androgen Receptor Agonist (Enobosarm) is a new way to suppress estrogen signaling. This works in the lab on all models of Er-positive MBC that have become resistant to AI plus CDK4,6 inhibitors. Actually has good side effects on muscle and bone, they are planning new trials this year to combine this with physician choice of other drug (phase 3) and also planning to move this drug to earlier stages of cancer due to favorable comparison with AIs. Importantly, this drug has been shown also to work on mutant forms of the estrogen receptor. There is a phase two trial combining this drug with Keytruda for AR+ forms of triple-negative cancers. A phase three trial for ER-positive patients is planned in the second quarter of this year, will be Enobosarm compared to exemestane (monotherapy).All of these drugs have just recently been gaining steam, would not be surprising if some MOs were not aware of them yet

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC68895...

https://www.globenewswire.com/news-release/2021/01...

https://www.fiercebiotech.com/research/veruas-tout...

Thanks for all the info, I have printed it along with the studies and hopefully my ONC will give me some time to go over these as possibilities, Also the ONC at Duke on the 1st Feb when I go there for the scans and meet with the research team for the Lymparza trial. I would so rather go the endocrine route, the last biopsy was 99% ER and 90% PR Her 2-neutral but when the fish test was run on the Her 2 it was negative. The issue is according to my ONC I am highly ER but my cancer is acting like a TN. I will push for more info on why they think I can’t try the SERM/SERD trials.