As evidence mounts that some hormone receptor-positive, HER2-negative breast cancer patients are being overtreated with chemotherapy, researchers are working to identify which patients can safely avoid it, and to expand the treatment options available to those who can. Atossa Therapeutics thinks endoxifen, the active metabolite behind tamoxifen, could be an important addition to that toolkit.
Since FDA approved tamoxifen in 1977, physicians have widely prescribed it to help prevent breast cancer recurrence after treatment, reducing recurrence by approximately 32% in the first four years after stopping treatment. It is widely credited as the first targeted treatment for breast cancer and the first drug to demonstrate that a five-year course of adjuvant endocrine therapy could reduce recurrence and improve survival.
“In order for tamoxifen to work, however, it requires heavy-duty work by the liver into about 22 different metabolites. Some are more active than others, and that’s a lot of burden on the liver,” said Janet Rea, senior vice president of R&D at Atossa Therapeutics.
It also presents a challenge because patients’ livers have different capacities for metabolic work, she said.
“If you’re not what’s called a good metabolizer (there’s a clinical definition for that; there are ultra-metabolizers and poor metabolizers) you’re not going to get the full benefit of tamoxifen, because your liver can’t process it appropriately,” Rea said.
Endoxifen, which Atossa is developing as a standalone therapy, is the most predominant active metabolite, she said.
“Rather than having the liver do all the heavy lifting to get to that metabolite, we’ve essentially done the liver’s initial work for it, so the drug is ready to go. It doesn’t require liver metabolism. It goes into the bloodstream and into the body in its active form,” Rea said.
The idea of getting to endoxifen without relying on the liver isn’t new. Since the early 2000s, researchers have understood that endoxifen, not tamoxifen itself, does most of the pharmacological work, and that the CYP2D6 enzyme responsible for the conversion varies widely between patients. However, turning this insight into a drug has taken far longer, partly because endoxifen’s active form breaks down when exposed to stomach acid. Atossa’s drug gets around this problem with an enteric coating designed to survive the stomach environment and only dissolve further in the gastrointestinal tract.
The case for treating fewer patients with chemo
Phase 3 data from the OPTIMA trial presented at ASCO this year found that 68% of high-risk patients could safely avoid chemotherapy. Among those who skipped chemo, five-year invasive breast cancer-free survival was 93.7%, compared to 94.9% for similar patients who received standard chemotherapy, a statistically non-inferior difference.
However, because the study recruited patients on a rolling basis over almost nine years, not all patients have been in the study long enough for a five-year follow up, widening the statistical confidence intervals around these results.
“OPTIMA, like all trials, has limitations. The biggest is that there is limited follow-up, with fewer than 40% reaching 5 years, which means that our confidence intervals are currently relatively broad,” Robert Stein, the trial’s chief investigator, said in his presentation at the 2026 American Society of Clinical Oncology (ASCO) Annual Meeting.
Rea still sees chemo being an important part of the treatment paradigm, she said, especially when a tumor is metastatic.
Where endoxifen could fit
Endoxifen could be used to treat breast cancer before surgical treatment, reducing the tumor’s activity.
“Studies show that some use of chemo prior to surgery does the same thing,” Rea said. “When you do that, your five-year outcome is excellent. Chemo is tough, so I think endoxifen offers a really good strategy to treat prior to surgery, because if you can shrink the tumor, you may need less invasive surgery, less reconstruction, and you’re also improving your five-year outcome.”
Endoxifen could also prevent the need for surgery at all for some patients. “I’m hopeful the data will ultimately show that if we treat with endoxifen and it helps reduce tumor size, maybe it won’t completely go away, but it would certainly allow for more watchful waiting rather than heading straight into the OR, there’s an opportunity there,” Rea said.
In a Phase 2 sub-study within the I-SPY 2 trial, 20 women with stage II/III ER-positive, HER2-negative breast cancer received low-dose oral endoxifen before surgery. The treatment produced a median Ki67 reduction from 10.5% at baseline to 5% by Week 3, a marker of tumor cell proliferation, along with substantial MRI-confirmed tumor shrinkage and a favorable safety profile, although no patients reached pathologic complete response at this dose.
Endoxifen could also be used after surgery, which is often when tamoxifen is prescribed. It could be an important option for male patients too, Rea said.
“A lot of times when men are diagnosed, they’re sicker and further along in their trajectory. If they do get treatment, chemo and so on, they’re limited in what they can take to prevent recurrence. Right now, that’s pretty much tamoxifen, and we think endoxifen would also be good for that patient population, and for those who can’t take aromatase inhibitors because of pre-existing conditions such as osteoporosis,” she said.
Other next-gen Selective Estrogen Receptor Modulators (SERMs) and Selective Estrogen Receptor Degraders (SERDs) are targeting the same patient population as endoxifen. Lasofoxifene, which LeonaBio licensed from Sermonix Pharmaceuticals, is a nonsteroidal SERM currently in Phase 3 for ER-positive, HER2-negative, ESR1-mutated metastatic breast cancer.
Stemline Therapeutics, a subsidiary of Menarini Group, received FDA approval in 2023 for elacestrant, the first approved oral SERD for breast cancer for postmenopausal women or adult men with ER-positive, HER2-negative, ESR1-mutated advanced or metastatic breast cancer who’ve progressed on at least one prior endocrine therapy.
Roche and Eli Lilly are also both developing oral SERDs. Roche’s giredestrant has posted a positive Phase 3 readout in the metastatic setting (evERA) and another in early-stage disease (lidERA), though a separate first-line metastatic trial (persevERA) missed its primary endpoint earlier this year.
Lilly’s imlunestrant recently received approval for ER-positive, HER2-negative, ESR1-mutated or metastatic breast cancer.
The road to biomarker-driven treatment decisions
“One of the things we’ve learned over the years is that one size doesn’t fit all when it comes to cancer therapy, and I think endoxifen would be widely used in the appropriate settings. It seems to be well tolerated, better tolerated initially than what we’re seeing with tamoxifen so far,” Rea said.
“It’s going to simply take data,” to get the FDA to accept a biomarker-driven treatment decision as grounds to skip chemo, Rea said.
“One thing we’re seeing from the FDA’s perspective is that they’re looking more at biomarkers and evidence-based mechanism of action. I think that’s something we’ll be able to leverage better than we could have a couple of years ago, and I think that will be really helpful,” she said.
There is some precedent for this, she added, in how breast cancer is classified by ER-positive or negative and HER2-positive or negative, which are now used to guide treatment decisions.
“There’s so much good research happening to really understand tumor dynamics, for lack of a better term: what makes it grow, what stimulates growth. I think within the next three to five years, we’ll have more medications, more drugs, more therapies that can address the specific metabolic or cellular attributes of a tumor and how best to turn it off,” Rea said.
In the next few years, “I think we’re just going to have more information, more tests to characterize the tumor, which will lead to more optimal treatment for each patient,” she added.
Filed Under: Oncology
