The ink was barely dry on the FDA approval letter for AstraZeneca’s Etcamah before the oral SERD suffered a key clinical setback.
Etcamah failed to significantly improve patients’ time before tumor progression or death compared with the aromatase inhibitor anastrozole for the first-line treatment of ER-positive, HER2-negative breast cancer, AZ said Friday. The readout comes from the Serena-4 phase 3 trial, in which all patients also received Pfizer’s CDK4/6 inhibitor Ibrance.
AZ noted a numerical progression-free survival improvement for the Etcamah regimen, but the outcome didn’t meet statistical significance on that trial’s primary endpoint.
Etcamah now joins Roche’s rival oral SERD, giredestrant, in missing the mark in first-line HR+/HER2- breast cancer. Previously, in the phase 3 persevERA trial, giredestrant plus Ibrance only showed a numerical 11% improvement over Novartis’ aromatase inhibitor letrozole and Ibrance.
Trying to infuse confidence into Serena-4 on AZ’s second-quarter earnings call back in July, AZ’s oncology and hematology R&D chief, Susan Galbraith, Ph.D., pointed to the study’s larger patient pool than persevERA, as well as a population enriched for endocrine sensitivity. Because oral SERDs exert their therapeutic effect through estrogen receptor signaling, they need tumors that remain vulnerable to endocrine manipulation to work.
The two failures now spell trouble for other oral SERD efforts in the first-line setting, such as Olema Oncology’s Opera-02 trial that combines its palazestrant with Ibrance.
The Serena-4 announcement came merely a week after the FDA’s surprise approval for Etcamah in another first-line setting. Rather than giving Etcamah from the outset, the accelerated approval allows the AZ drug to be used in combination with a CDK4/6 inhibitor upon detection of ESR1 mutation during first-line aromatase inhibitor and CDK4/6 therapy—prior to traditional radiographic disease progression.
In a Friday statement, Galbraith said the Serena-4 readout “reinforces the importance of ESR1 testing for patients on first-line therapy.”
The FDA had initially resisted that novel first-line switch approach because of a design flaw in AZ’s Serena-6 trial, but the agency came around to overrule a similarly negative advisory committee opinion.
However, there’s a twist: In clearing Etcamah, the FDA has required AZ to run a separate randomized trial, essentially asking the company to re-do Serena-6 but with an optimal design. The agency specifically asked that AZ compare changing therapy to Etcamah during first-line treatment to using the oral SERD upon progression in the second-line setting, according to the FDA’s approval letter.
That trial, along with the final overall survival results from Serena-6, form the FDA’s accelerated approval requirements to verify Etcamah’s benefit in its current indication. According to the FDA’s letter, AZ plans to finalize the new study’s protocol by April 2027.
That means at least the current Serena-4 flop will not affect Etcamah’s accelerated approval status.
Prior to Etcamah, oral SERDs have been approved as second-line HR+/HER2- breast cancer treatments but only for those whose tumors carry ESR1 mutations, as they’ve shown no clear benefit in those without the abnormalities.
Untreated HR+/HER2- breast cancers rarely carry ESR1 mutations that could give oral SERDs a biological advantage over standard therapies. Over time, cancer cells adapt to anti-estrogen treatment by developing ESR1 mutations, which turn the estrogen receptor on without the need for hormones, making standard aromatase inhibitors ineffective.
Existing CDK4/6 inhibitors are already very potent, and “you don’t see early on what is really an effect of an endocrine manipulation,” Roche’s deputy chief medical officer, Stefan Frings, M.D., Ph.D., told Fierce when explaining giredestrant’s first-line fail during ASCO 2026.
Despite the first-line setback, Roche’s pharma chief, Teresa Graham, has argued that giredestrant’s multibillion-dollar peak sales potential remains intact by pointing to its opportunity as an adjuvant therapy for early-stage cancer.
Similarly, Eli Lilly’s oncology chief, Jake Van Naarden, has also called the adjuvant setting what “this entire class of medicines was ever resourced” for. The Indianapolis pharma has its oral SERD, Inluriyo, currently approved as a second-line option.
In its press release on Friday, AZ also highlighted its two phase 3 trials, Cambria-1 and -2, designed for patients at both intermediate and high risk of recurrence in the adjuvant setting. The two studies together encompass roughly 10,000 patients and are evaluating Etcamah as a monotherapy, in combination with CDK4/6 inhibitors and following CDK4/6 treatment in early HR+/HER2- breast cancer.