Once Upon a Time, in a Lab Far Far Away

Our story begins four years ago, when Kaitlyn Andreano, then a PhD student in the Department of Pharmacology and Cancer Biology training in McDonnell’s lab, uncovered a novel use for an old osteoporosis drug called lasofoxifene — a possible treatment for metastatic breast cancer.

But first, the backstory.

Lasofoxifene, a type of endocrine or hormonal therapy, is a selective estrogen receptor modulator (SERM). In breast cancer, SERMs work by sitting in the estrogen receptors in breast cells, thus blocking the effects of estrogen in the breast tissue. However, paradoxically, they also function as estrogens in bone and protect against osteoporosis.

Lasofoxifene was first discovered in 1992 through a research collaboration between California-based Ligand Pharmaceuticals and Pfizer Inc. McDonnell, a young researcher with Ligand at the time, was part of the team developing the drug to treat osteoporosis in women as a result of estrogen loss in menopause.

“Estrogens are generally very protective against bone loss, but people don’t like the side effects of those drugs,” said McDonnell, a nationally renowned cancer scientist who began his three- decade research career studying bone biology. “When I was a young guy with dark hair, I figured out how to manipulate the estrogen receptor to identify drugs that inhibited the negative actions of estrogen in breast cancer cells, but which were bone protective. Building on this discovery, and upon arriving at Duke in 1994, I set out to identify ER (estrogen receptor)—targeting drugs that worked better than those available and that would be particularly effective in the treatment of metastatic breast cancer.”

Seventy to eighty percent of the more than 270,000 invasive breast cancers diagnosed annually in women in the United States, are estrogen receptor-positive (ER+).

Endocrine therapies are standard-of-care for these patients. This includes SERMS (drugs in the same class as lasofoxifene) and selective estrogen receptor degraders (SERDs) — both of which target the wild-type estrogen receptor present in cancer cells and in the body’s immune cells — and aromatase inhibitors, which suppress estrogen synthesis.

More than 1.5 million women in the U.S. are currently on endocrine therapies for breast cancer — either as monotherapies or in combination with other drugs such as targeted therapies and/or chemotherapies. These drugs and drug combinations have been found to work well, in some cases for many years, until they don’t. Cancer is smart. Mutations can develop in breast cancer cells that render the best therapeutic strategies ineffective. Metastasis, cancer that has spread to distant organs, is the major cause of breast cancer death. While more and more women are living with metastatic breast cancer (upwards of 150,000), 42,000 die of MBC each year.

A few years ago, McDonnell explained, it became apparent to researchers across the world that estrogen receptor mutations that developed in breast cancer cells as the cancer spread — ESR1 mutations — were one cause of this acquired resistance to endocrine therapy and a likely driver of that breast cancer spread. Upon close inspection, it was discovered that between 30% to 40% of patients with ER+ breast cancer, especially those who’d been extensively pretreated with aromatase inhibitors, would go on to develop an ESR1 mutation.

“This ignited what I would call a whole cottage industry around these mutations, with scientists trying to develop drugs that would target them just as well as the endocrine therapies that targeted the wild-type estrogen receptor protein,” said McDonnell.

Eureka!

In early 2016, a DCI physician scientist who’d completed her doctoral training in McDonnell’s lab — Stephanie Gaillard, MD, PhD — came across an ESR1 mutation in an ovarian cancer. Gaillard shared this with the lab, believing McDonnell might have some ideas as to how to leverage this information to help patients whose cancers harbored these ESR1 mutations.

Kaitlyn Andreano, a graduate student in McDonnell’s lab, took on the project.

“Kaitlyn decided to collect or synthesize nearly every endocrine drug that had ever been made, which is easy enough to do in my lab because we've been involved in the development of most of them, and she screened and found that lasofoxifene alone was effective against pretty much all of the ESR1 mutations, it didn't seem to care,” said McDonnell. “We knew that if you developed an ESR1 mutation, you would be resistant to all the endocrine therapies we have, but lasofoxifene was different. That was the discovery. As it turned out, the story with mutations is a lot more complex than people make it out to be….”

Predicting that lasofoxifene would work in ER+ breast cancer, the lab filed what’s called “an invention disclosure” on May 25, 2016.

Next, Andreano pushed for a utility patent. Without this, she and McDonnell assessed, the “old drug” would never be developed.  Because the discovery was made in a Duke lab, Duke University filed, in Oct. 2017,The patent was issued in April 2019 with Andreano, Ching-Yi Chang, PhD, MSPH, (research associate professor of Pharmacology and Cancer Biology and McDonnell Lab member), Gaillard, and McDonnell listed as inventors. Lasofoxifene looked promising — where other endocrine therapies had failed — for the treatment of metastatic breast cancer in patients with the ESR1 mutation. Next, to translate these findings in the lab to clinical use.

The owner of the U.S. rights to lasofoxifene at the time was Ohio-based Sermonix Pharmaceuticals.

The company’s CEO David Portman, MD, had acquired the rights to the drug in February 2015, just a couple months after he and his wife Miriam Davidson Portman, MD, founded the company.

Portman — an OB-GYN by training and clinical researcher in women’s health, sexual medicine and menopause — had been principal investigator for Pfizer during some of their phase two and phase three studies of lasofoxifene in osteoporosis and he’d also consulted on the drug’s gynecological effects, including the alleviation of vaginal dryness/atrophy in menopause that can cause painful intercourse and sexual dysfunction. 

He knew that Pfizer had received European Union authorization in 2009 to market lasofoxifene as a treatment for osteoporosis in postmenopausal women, but chose not to market it after acquiring Wyeth and a competing drug — a similar SERM designed to treat osteoporosis called Conbriza (bazedoxifene). He was also aware that the three-year marketing authorization had lapsed in 2012 and the rights to lasofoxifene had reverted to Ligand.

“This particular compound was looking for a good home,” said Portman. “We were fully prepared to try to move it forward in what had already been studied in menopause and osteoporosis, to pick up where Pfizer left off, but we came across this data (from the invention disclosure filed by the McDonnell lab) about a year into our efforts and this seemed to be a much more important area of unmet medical need. We had no idea, when we started, that we’d end up in the metastatic breast cancer space.”

On Nov. 8, 2016, even before a patent was issued, Sermonix and Duke’s Office of Licensing and Ventures (Duke OLV) came to an agreement whereby the company would acquire exclusive rights to further develop what was Duke’s intellectual property, and, if FDA-approved, commercialize lasofoxifene to treat advanced and metastatic breast cancer. Bryan Baines, RPh, director of scientific collaboration with OLV, facilitated the contract.

Sermonix also expanded its agreement with Ligand from U.S. rights to worldwide licensing rights, clearing the way for a launch of an international multi-site clinical trial — Evaluating LAsofoxIfeNe in ESR1 Mutations trial, the ELAINE Study, named for Portman’s sister-in-law Elaine Davidson Nemzer, MD, a child psychiatrist who passed away from metastatic breast cancer 20 years previous at the age of 47.

On Track

The ELAINE study opened last year— enrolling its first patient in September 2019 at the Mayo Clinic in Rochester, Minnesota — as a phase 2 open-label study with Fast Track designation by the FDA. (There was no need for a phase 1 trial since dosing and safety were already evaluated in the studies of lasofoxifene for osteoporosis.)

The trial is designed to evaluate the activity of lasofoxifene relative to fulvestrant for the treatment of postmenopausal women and premenopausal women with locally advanced or metastatic ER+/HER2-  breast cancer and an ESR1 mutation whose disease has progressed despite treatment with the standard-of-care therapy — an aromatase inhibitor in combination with a CDK 4/6 inhibitor. [Aromatase inhibitors, which suppress estrogen synthesis, include anastrozole, letrozole, or exemestane. Cyclin-Dependent Kinase 4/6 inhibitors, which operate by interrupting the growth of cancer cells by targeting the CDK4 and CDK6 enzymes that are important in cell division, include abemaciclib, ribociclib, and palbociclib.]

According to Sermonix, there are currently 29 U.S. and five international sites open. Duke Cancer Institute opened a study site in in September 2020 and enrolled its first patient on Nov. 9 this year, with DCI medical oncologist Sarah Sammons, MD, as the clinical principal investigator.

The company’s goal, Portman said, is to fully enroll the study (100 patients—two to three per trial site) by early 2021 and have phase 2 results data to report to FDA regulators by early 2022.

Every ER+/HER2- breast cancer patient with advanced or metastatic disease whose cancer has progressed through an AI and CDK 4/6 combination therapy at the trial sites have the opportunity to be screened for the trial (with some exclusions, including men with breast cancer and women with metastasis to the brain). Most patients with metastatic ER+/HER2- breast cancer will undergo standard of care next generation sequencing in order to determine the optimal next treatment regimen after progression on endocrine therapy and CDK4/6 inhibitors. If they have not, as part of the screening process, each patient’s tumor can be biopsied and sequenced to determine if she harbors an ESR1 mutation.

Half of the enrolled patients will receive a 5mg oral dose of lasofoxifene (a selective estrogen receptor modulator) and the other half will receive a monthly intramuscular injection of fulvestrant, a selective estrogen receptor degrader (SERD) and the only approved endocrine therapy that has shown some efficacy in targeting ESR1 mutations.

Fulvestrant is considered the current “gold standard” for treating ESR1 mutations, said Sammons, but it's far from ideal, with a median progression-free survival between two and four months as a single agent.

“A nice thing about this trial is that we're able to utilize the strength of our molecular tumor board,” said Sammons, who hopes to accrue up to 10 patients. “It’s going to be efficient because when patients get genomic sequencing as standard of care, MrT (DCI’s in- house electronic Molecular Registry of Tumors) will flag patients who have an ESR1 mutation and automatically email/notify the provider of their possible eligibility.”

This testing could even reveal another, potentially druggable mutation.

Added Bonus

Often, when patients enroll in a trial, they have little information about the drug’s potential side effects. In the case of lasofoxifene, it’s side-effects are well characterized and appear to be quite well tolerated.

“A wonderful thing for breast cancer patients is that lasofoxifene is very patient friendly,” said Sammons. “It actually improves vaginal dryness and sexual health and strengthens bone. We don't often have a drug in advanced breast cancer that has a favorable side effect profile, right? That's very appealing to our patients.”

This is in stark contrast to most endocrine therapies, which tend to cause vaginal atrophy/dryness, bone loss with an increased fracture risk, and early menopause in pre-menopausal women.

Sammons said if the ELAINE Study yields positive results, the next step will be to combine lasofoxifene with other targeted agents. This is already in progress with the newly open ELAINE II clinical trial combining lasofoxifene with the CDK4/6 inhibitor abemaciclib (Verzenio).

“Endocrine therapy is the important backbone,” she explained. “We know that endocrine therapy works better, in general, when you add an optimal targeted agent such as CDK4/6, mTOR, or PIK3CA inhibitors.”

With Duke finally on board as a clinical site, this bench-to-bedside story has been written, but it’s not finished. McDonnell and Sammons, for the sake of the thousands of metastatic breast cancer patients waiting for their next line of therapy, hope this story will have a happy ending.

“Treating metastatic breast cancer patients is my passion,” said Sammons. “Providing them the most up to date and compassionate care and developing novel therapies for advanced breast cancer that will improve outcomes are really why I am here at Duke.”

Lasofoxifene is not available off-label, i.e. for Expanded Access, or Compassionate Use, nor is Sermonix accommodating any “Right to Try” requests at this time. For more information about the ELAINE trial and enrollment at Duke Cancer Institute, contact the Breast Oncology Research team at 919.660.1278.

Disclosures

Sarah Sammons, MD, has done consulting for Novartis, Foundation Medicine, Sermonix, Astra Zeneca and Daiichi Sankyo. She receives research funding to her institution for clinical trials from Astra Zeneca, BMS, Eli Lilly, and Sermonix.

Donald McDonnell, PhD, is a consultant and has stock ownership in G1 Therapeutics and Zentalis. He receives royalties from Radius Health and could receive royalties through Duke associated with the licensing of lasofoxifene. He receives research support from Novartis. 

Ching-Yi Chang, PhD, MSPH, could receive royalties through Duke associated with the licensing of lasofoxifene.

No longer at Duke:

Kaitlyn Andreano, PhD, earned her PhD from Duke in May 2020 and is currently a Specialist, Project Management and Clinical Pharmacology, with Nuventra Pharma Sciences. She could receive royalties through Duke associated with the licensing of lasofoxifene.

Stephanie Gaillard, MD, PhD, is currently an Assistant Professor of Oncology with Johns Hopkins Sydney Kimmel Comprehensive Cancer Center. She joined Hopkins in early 2017. She could receive royalties through Duke associated with the licensing of lasofoxifene.