Roche's oral SERD flunks phase 3 breast cancer test

Roche's recent run of positive study results with giredestrant has come to an end with the failure of the persevERA trial in HR-positive, HER2-negative advanced breast cancer.

The oral selective oestrogen receptor degrader (SERD) was unable to extend the time to disease progression or death significantly compared to standard anti-oestrogen therapy letrozole, with both drugs given as a combination regimen with Pfizer's CDK4/6 inhibitor Ibrance (palbociclib), as first-line treatment for endocrine therapy-sensitive patients with this form of breast cancer.

Giredestrant has already been submitted for approval in the US as a combination regimen with everolimus as a second-line treatment for ESR-1-mutated HR+/HER2- advanced breast cancer, based on the results of the evERA trial.

The decision to limit the filing to ESR-1-mutated cases only was made despite Roche reporting a positive result for the drug in an all-comer population in the evERA trial as well, raising hopes that it could have a broader label than the current two marketed drugs in the class - Menarini/Stemline's Orserdu (elacestrant) and Eli Lilly's Inluriyo (imlunestrant).

Roche's drug, meanwhile, also showed efficacy in the early post-surgical (adjuvant) setting in the lidERA trial, an indication due to be filed shortly, breathing new life into a programme whose prospects looked rocky after a failure in the mid-stage acelERA trial.

The narrower second-line filing and first-line miss will nevertheless peg back sales expectations for the drug, which has been pitched as a multibillion-dollar prospect, and shares in Roche fell more than 5% on the news this morning.

In a statement, Roche said that there was a numerical trend in favour of giredestrant in persevERA, and the company's chief medical officer, Levi Garraway, said he remains "confident in the potential of giredestrant to become a new standard-of-care endocrine therapy in early and advanced [HR-positive] breast cancer."

Roche is running another phase 3 trial in the front-line setting – pionERA – which is enrolling patients whose cancer has proved resistant to endocrine therapy in the adjuvant setting and is due to read out in 2027.

Meanwhile, Garraway said Roche plans to double down on the positive results with the drug in lidERA - a statistically significant improvement in invasive disease-free survival (iDFS) with giredestrant versus standard-of-care endocrine therapy – and will run additional studies. Giredestrant is the first oral SERD to show a benefit as an adjuvant treatment.

"We believe there is a path forward for combining giredestrant with a CDK4/6 inhibitor in the adjuvant setting," he asserted.

AstraZeneca has also filed an oral SERD, camizestrant, targeting use of the drug in patients with advanced HR-positive breast cancer who have developed ESR1 tumour mutations in first-line therapy, looking at its use in combination with CDK4/6 inhibitors. A decision on that application is due in the first half of this year.