FDA Accepts Roche's Giredestrant Filing for ESR1-Mutated Breast Cancer

The FDA has accepted an approval filing for Roche's oral SERD giredestrant, but not in the broad all-comers ER-positive breast cancer population that last year's phase 3 Evera study readout seemed to promise. The filing is restricted to the ESR1-mutant population, with a decision expected by December 18, 2026.

Last September the company reported a statistically significant benefit in both ESR1-mutant patients and the overall population in Evera, raising hopes that giredestrant could become the first oral SERD available beyond the ESR1-mutant population. But Evera had been enriched for patients with ESR1-mutant disease, raising questions about how much of the all-comers benefit was driven purely by that subgroup.

The FDA hasn't bought the all-comers argument, apparently forcing Roche to confine giredestrant's US filing to the ESR1 biomarker-defined subgroup. This effectively places giredestrant alongside rival oral SERDs, albeit with a slight wrinkle in the potential label to reflect the trial's post-CDK4/6 inhibitor setting and combination with everolimus.

Evera evaluated giredestrant plus everolimus versus endocrine therapy plus everolimus in ER-positive, HER2-negative breast cancer patients who had failed CDK4/6 inhibition. Data presented at ESMO in October showed that giredestrant plus everolimus reduced the risk of progression or death by 44% in the intention-to-treat population, with a median progression-free survival of 8.8 months versus 5.5 months for endocrine therapy plus everolimus.

Among the ESR1-mutant patients, median PFS extended to 10.0 months compared with 5.5 months in the control arm, a 62% risk reduction. In ESR1 wild-type disease, by contrast, the median difference was just six days: 5.7 months versus 5.5 months. Although the hazard ratio of 0.84 and the separation of the curves suggested a benefit, the absolute gain appeared modest.

That dynamic closely mirrors the experience of Menarini's Orserdu. This FDA-approved oral SERD also showed a benefit in an all-comers population in the Emerald trial. But Emerald too had been enriched for ESR1-mutant disease, and the FDA ultimately restricted approval to the ESR1-mutant population. An exploratory analysis of PFS in patients without ESR1 mutations showed a hazard ratio of 0.86, a very similar number to what Roche achieved.

With Inluriyo, Lilly's oral SERD, also approved in ESR1m patients, and Pfizer and Arvinas turning away from their project vepgestrant, this leaves Olema as the only company still pursuing a potentially broader population. Its phase 3 Opera-01 trial is expected to read out in the second half of this year.

AstraZeneca is pursuing a different tack. The company filed its oral SERD camizestrant on the basis of the Serena-6 trial in first-line patients who develop ESR1 mutations but have not progressed after treatment with CDK4/6 inhibitors. That filing has a PDUFA action date set for the first half of this year.