Decades Of Study Reveal Major Misconceptions About Oral SERDs

  • Fulvestrant, a long-standing injectable SERD used monthly for HR+ breast cancer, remains a cornerstone therapy — and its evolving use may help unlock access to additional treatment options.
  • Dr. Neal Vasan, director of breast cancer translational research at NYU Langone, says oncologists assumed fulvestrant would be more bioavailable, better tolerated, and equally effective across all patients, regardless of estrogen receptor mutation status. “But those assumptions turned out to be wrong,” he says.
  • Fulvestrant’s unexpectedly strong impact after primary treatment is reshaping assumptions, showing that a drug with modest metastatic benefit can deliver meaningful gains in the adjuvant setting and prompting a rethink of how new therapies are developed.

For more than two decades, fulvestrant — a selective estrogen receptor degrader (SERD) delivered through two deep intramuscular injections in the buttocks every month — has been a familiar presence in the treatment of hormone receptor-positive (HR+) breast cancer.

Its limitations were well known: painful administration, slow onset, and notoriously poor bioavailability, meaning not much actually makes it to cancer cells once injected into the body. Yet its clinical impact has proven surprisingly durable.

Dr. Neil Vasan, a breast oncologist and physician‑scientist at NYU Langone who treats patients while running a laboratory focused on new therapeutic strategies, says the arrival of oral SERDs was once seen as a straightforward evolution.

“The thought was that if we could get an oral version of this drug — you’d swallow it, it would go through the liver, undergo first‑pass metabolism, and sort of go everywhere in the body,” he explains.

The field assumed these agents would be more bioavailable, better tolerated, and equally effective across all patients, regardless of estrogen receptor mutation status.

“But all three of those assumptions turned out to be wrong,” he says.

Fulvestrant’s Surprising Influence

Despite fulvestrant’s delivery challenges and pharmacologic constraints, its influence is now extending into the adjuvant setting — a potential paradigm shift in care.

“A drug like this that has such a small benefit in the metastatic setting would not be expected to have a bigger effect in the adjuvant setting,” Dr. Vasan says. “So, the fact that we’re already seeing a magnitude of benefit in the adjuvant setting … is really changing how we’re thinking about drug development as well.”

In other words, fulvestrant’s unexpected strength is expanding the treatment possibilities. If a poorly bioavailable injectable SERD can move the needle after primary treatment, what might optimized oral SERDs accomplish when deployed earlier in the disease course? These are the thoughts Dr. Vasan is helping to put into the broader conversation within the oncology community.

Where Oral SERDs Stand Today

Despite the excitement, Dr. Vasan is clear about the current boundaries. In metastatic breast cancer, oral SERDs are approved only for patients whose tumors carry ESR1 mutations — a resistance mechanism that emerges after long‑term hormone therapy.

“Right now in the metastatic setting, the approvals are all in women whose breast cancers have ESR1 mutations,” he says. “If patients don’t have an ESR1 mutation, we’re not going to be giving them an oral SERD as standard of care — possibly on a clinical trial.”

This precision‑based restriction reflects the very assumptions the field once got wrong. Oral SERDs do not behave uniformly across all patients. They are not universally well tolerated, and their bioavailability varies in ways that continue to surprise researchers.

Currently, there are several trials studying the role of oral SERDs in this setting, including SERENA-6 (camizestrant), EMBER-3 (imlunestrant), ELECTRA (elacestrant), persevERA (giredestrant), and lidERA (giredestrant adjuvant).

A New Chapter In Endocrine Therapy

Still, fulvestrant’s unexpected performance in the adjuvant setting has opened the door to a broader re‑evaluation of SERDs as potential frontline tools capable of reshaping long‑term outcomes.

For Dr. Vasan, this moment represents a rare opportunity: a chance to rethink endocrine therapy from the ground up, informed by both the successes and the lessons learned from fulvestrant.

Oral SERDs may not have fulfilled every early expectation, but they have sparked a deeper understanding of estrogen receptor biology, and more uses of this treatment may emerge in the future.