Are you currently (or have you been) in a Clinical Trial?

@cure-ious

Interested in your comment about Xeloda as a buffer. Facing an impending treatment change after almost 4 years of Kisqali as my CEA (which is predictive for me) has risen 12 points. I don't believe that Kisqali stopped working, but I was forced to take a 1 month and then a 2 month break in the second half of 2025 for antibiotic treatment for persistent diverticulitis. Scans in two weeks and MO's plan is Verzenio, Affinitor, Xeloda and then circle back to Kisqali or maybe even Ibrance if I can still tolerate them. My Tempus biopsy showed no actionable mutations, just something called "missence variations".

I recall you discussing trials for a CDK2 and a CDK4 inhibitor. Have either of those been approved and would they have lesser toxicity because they target a single area?

Another approach worth considering is whether Xeloda could be postponed even further, for example by combining Verzenio or Ibrance with newer oral SERDs that are more potent than Faslodex or AIs.

For example, the recent Verzenio and Elascestrant trial showed the combination was effective, regardless of ESR1 or PIK3CA mutation status, So whereas Elascestrant as monotherapy was only approved for cancers with ESR1 mutations, the combination (Elascestant +Verzenio) worked for everybody, and the data look great (73% stable or better for 6 months), here are some details from AJMC.

The pooled analysis reported new safety and preliminary efficacy for elacestrant combined with abemaciclib in combination with patients with prior endocrine therapy and CDK4/6 inhibitor exposure from both the ELECTRA (NCT05386108) and ELEVATE (NCT05563220) studies.

Participants (N = 42) were administered elacestrant 345 mg once a day combined with abemaciclib 150 mg twice daily. The population comprised all women, with 60 as the average age. Metastatic sites were mainly visceral (71%) with ESR1 mutations (53%).

The responses and clinical benefits patients (n = 38) had with elacestrant combined with abemaciclib were examined among efficacy-evaluable participants. Comparable safety and efficacy were evident in the complete response (5%), partial response (13%), stable disease (66%), and progressive disease (16%) rates.

Treatment-emergent adverse events (TEAEs) included diarrhea (83%), nausea (64%), vomiting (41%), fatigue (36%), neutropenia (33%), anemia (24%), constipation (21%), and decreased appetite (21%). All of the TEAEs were grade 3 or lower.

The median PFS was 8.7 months among all patients with ESR1-mutated tumors and 7.2 months in tumors with ESR1 mutations not detected. Patients who received prior endocrine therapy with CDK 4/6 inhibitors for 12 months or more had an average PFS of 16.6 months.

Patients with prior endocrine therapy combined with CDK4/6 inhibitors had consistent safety outcomes with elacestrant and abemaciclib therapy. Despite ESR1-mutation status, elacestrant combined with abemaciclib showed clinically meaningful efficacy rates.

I have never been on a Clinical Trial. I have had progression on my latest scans and considering clinical trials. My MO staff suggested this one: NCT07062965. Any ideas on the drug—- a KAT6 inhibitor.

@candy -678. Yes, that's a good trial from Pfizer! Its not great monotherapy but works well with Fulvestrant (side effects neutropenia plus I think it might make foods taste metallic? ) and so they went straight from Phase 1 to Phase 3. Also consider a popular Phase 1 trial from the Italian firm Meninari, where an AI-designed Kat6i is being combined with Elacestrant (Orserdu) , an oral SERD:

https://clinicaltrials.gov/study/NCT06638307

And also this one being combined with the Palazestrant SERD

https://clinicaltrials.gov/study/NCT06784193

Interesting about immunotherapy, timing has a big effect:

"In the trial, clinicians randomly assigned patients with late-stage lung cancer to receive the first four cycles of their drug treatment — an immune-targeted “checkpoint inhibitor” plus more conventional chemotherapy — either in the morning to early afternoon or later in the day.

Despite otherwise identical drug regimens, patients treated earlier went nearly twice as long without their tumors growing bigger or spreading — about 11 months in a typical case, compared with 6 months — and lived nearly a year longer on average, surviving roughly 28 months versus 17 months in the late-treatment group.

Blood tests from the study offered hints as to why. Patients treated earlier in the day showed signs of a more active immune response, with higher levels of cancer-fighting T cells than those treated later. Notably, however, earlier dosing did not increase rates of immune-related side effects, suggesting that timing may boost the immune system’s attack on tumors without raising the risk of autoimmune reactions.

Taken together, the results point to a simple scheduling change as a low-cost way to improve outcomes for cancer patients without altering drugs, doses or other treatment parameters."

@candy -678

Oh, great, I was just coming on to ask if there would be a liver biopsy, as you know the biggest help is getting good data on the cancer at progression- will there be a new Guardant as well? I'm confused about the subtype switching, does it mean that both original and new cancer subtypes exist, and that once you beat back one the other becomes more prominent? The liver biopsy can say what mutations are clonal, which is important, presumably that includes the BRCA1 mutant? Is the cancer also Her2-low?

The trial testing Orserdu with CDK4,6i showed it works equally well on ESR1 mutant and non-mutant cancers, so if the cancer is ER-positive but not ESR1 mutant, you could still be eligible for that when it gets thru the FDA.

About the immunotherapy, there are some alternative approaches in trials because of the dangerous side effects that can happen. Also they are testing Enhertu-like drugs where the Her2 antibody is linked to a targeted drug, rather than a chemo, hoping to avoid the interstitial lung disease problem seen with ADCs.

You have gone a really long time every line, which hopefully bodes well for subsequent responses, just need the data to decide which way seems best.

New ATR inhibitors and WRN inhibitors look really good for BRCA1 mutant cancers:

https://www.youtube.com/watch?v=f1LClv5DXs8&t=338s

Cure-ious- They did the Guardant liquid biopsy the other day. I already have those results. Nothing actionable, and no ESR1 mutation. Sigh…. But we are doing the tissue biopsy on April 6 and doing Foundation One testing on that.

"subtype switching" as you said???? What do you mean? The ER going from positive to negative? It did, but I am wondering if that was heterogeneity of the tumor that they sampled.

I will look for the word "clonal" when looking at test results. I have never seen it stated that way.

I am HER2 low—— 2+.

Are there any other options for a Fulvestrant type drug only oral? From what I am seeing the orals have to have an ESR1 mutation.

I will watch your links you posted.

Cure-ious- So am I correct in my thinking: Fulvestrant is the only SERD approved for everyone, even those with no ESR1 mutation? And that there is no oral SERD approved for those without an ESR1 mutation? Since I do not have an ESR1 mutation, I can only use AI's or Fulvestrant for HR+ hormone therapy? ——— Currently, not in trial.

The company that makes my trial drug has new PARPinhibitor (SNV-1421) that only inhibits PARP-1 and so has fewer side effects, and just announced 10 days ago they've gotten a good WRN inhibitor, which will head into trials, most WRN inhibitors I see are used for MSI-hi? Do you know MSI status?

Candy, here are some trials with Saruparib, you did so well on first-gen PARPi, maybe just keep it going:

"Saruparib (AZD5305) is a highly selective, next-generation PARP1 inhibitor showing promising activity in patients with homologous recombination repair (HRR) mutations who have previously tried other treatments, including first-generation PARP inhibitors. It is designed to be more targeted and less toxic, potentially overcoming resistance mechanisms seen with older inhibitors."

EvoPAR-Breast01 (NCT06380751) A Phase 3 trial studying saruparib plus camizestrant versus standard CDK4/6 inhibitors and endocrine therapy in patients with HR-positive, HER2-negative, BRCA1/2, or PALB2m advanced breast cancer.

PETRA Study (NCT04644068): A Phase 1/2a, first-in-human trial investigating the safety, tolerability, and efficacy of saruparib in patients with advanced solid tumors, including BRCA-mutated breast, ovarian, pancreatic, and prostate cancers.

Cure-ious- In your last post, where did you get the statement you quoted, "Saruparib is a highly selective…. showing promising activity…who have tried other treatments, including first generation PARP's"? Because I called my clinical trial coordinator to ask about the trial NCT 06380751 and she said that it is for newly diagnosed MBC that has not been treated yet. Upon looking further at the trial exclusion criteria, it says "prior treatment for metastatic disease is not permitted". So this trial will not work for me.

Cure-ious- I was already thinking of the option of revisiting a CDK 4/6 - maybe Verzenio with Fulvestrant (I was initially on Ibrance and Letrozole). So if I got that arm I was ok with that.

I am going to have to reread the trial— I am new at reading trials. I too, along with my clinical trial coordinator, thought it said "no previous treatments in the metastatic setting".

I have no idea if KAT6 meds work on BRCA mutant cancers.

I thought that cancer goes different pathways when there is progression. I.e. bypasses the hormone pathway and goes the BRCA pathway or the PIK pathway. That is why we can move to other treatments. I didn't think you have to stay on the same pathway forever— once BRCA then must stay on the BRCA though process.

Hi Candy- Not to belabor the point here, but normally in a clinical trial listing like this, if no prior PARPi was allowed, it would say so outright, at or near the top of the list of exclusions.

Are you referring to the part that says: "Prior treatment with systemic anti-cancer therapy for locoregionally recurrent or metastatic disease is not permitted, apart from treatment with ET up to 28 days before randomisation"

My reading of that sentence is that you have to do a washout of all drugs, except for ET, for 28 days before starting the trial. Granted, a comma after ET would have helped convey the meaning, but if you read it otherwise sure it could mean firstline only, but then why put in the weird bit about 28 days?.

But regardless, trials have all kinds of exclusions they forget to put down or decide to add later, so if you were interested in the trial, its easier to go see the doctor heading the trial and ask if you are eligible and also find out if there are other trials they would recommend.

This trial would give you a stronger ET (Camizestrant, which is great) paired with Suraparib, a next-gen PARPi that is only hitting PARP1 (ie, not the other PARPs) and so stronger with fewer side effects. You might be resistant to it, and for that you need the new biopsy/Guardant info, but there are many cases where that works, even just taking ET, for example when people progress on fulvestrant and then go a long time on an oral SERD, etc

@cure-ious When I was first diagnosed over three years ago I was accepted for the Breast09 trial. I was randomised and received standard of care. Then just under a year ago they discovered I had Brain Mets. I was taken off trial because of progression, and ironically I was put on to Enhurtu!

What I don’t understand is why not all of the Breast09 results have been published? It seems that in the USA they are using Enhurtu along with Pertuzumab as first line treatment. They have yet to publish the trial results for the arm using Enhurtu alone.

I am just wondering on your thoughts about this? I live in the UK and wonder if I should be on Pertuzumab as well, this is my second line of treatment.

@cure-ious I was lucky that on THP I had a near complete response, six months into treatment I had a Mastectomy. All my lymph nodes were removed and I received 15 sessions of Radiotherapy.

My Oncologist said at the time I got randomised to standard of care, that maybe it was better to receive THP at that stage. Otherwise where would I go after receiving Enhurtu? I tolerated THP well. Unfortunately it did not cross the blood to brain barrier. Had I received Enhurtu at the beginning would Brain mets not have developed? My current Oncologist remarked that I am receiving the best treatment available (Enhurtu). I find It is a much harder drug to tolerate.

I have been watching a phase 1 trial Zanabrutinib, because with Brain mets I feel that I have less future options available. Of course I will continue on Enhurtu for as long as I can.