Data cues up AZ oral SERD filing in first-line breast cancer

AstraZeneca could become the first company to bring an oral selective oestrogen receptor degrader (SERD) drug to market as a first-line treatment for breast cancer after camizestrant hit the mark in a phase 3 trial.

Top-line data from the SERENA-6 trial showed that camizestrant reduced the risk of disease progression or death compared to the standard-of-care regimen in previously untreated patients with HR-positive, HER2-negative advanced breast cancer whose tumours express ESR1 gene mutations that are linked to resistance to hormonal therapies.

The study compared camizestrant in combination with CDK4/6 inhibitor drugs – such as Pfizer's Ibrance (palbociclib), Novartis' Kisqali (ribociclib), or Eli Lilly's Verzenios (abemaciclib) – to regimens of CDK4/6 inhibitors with aromatase inhibitors like anastrozole or letrozole.

According to one of the study's principal investigators – François-Clément Bidard of the Institut Curie & UVSQ/Université Paris-Saclay – the results are "an important step forward for patients, and a potential shift in clinical practice."

AZ said it will now approach regulatory authorities around the world with the data, setting up the possibility of an approval that would leapfrog the only other oral SERD that has reached the market so far – Menarini/Stemline's Orserdu (elacestrant) – which was cleared as a second-line therapy for HR-positive, HER2-negative advanced breast cancer with ESR1 mutations in 2023.

In AZ's fourth-quarter results conference, chief executive Pascal Soriot reiterated the company's view that camizestrant has the potential to become a $5 billion-a-year product at its peak.

Around 70% of all metastatic breast cancer cases are HR-positive and HER2-negative, and ESR1 mutations are found in up to 40% of these tumours. That suggests there should be plenty of eligible patients for oral SERD therapy – assuming ESR1 testing becomes more commonplace – and AZ has estimated that the SERRNA-6 population represents around 30% of all endocrine-sensitive first-line patients.

Competitive position

Among potential rivals, Sanofi's amcenestrant – which was in the lead among the oral SERD class at one point – was discontinued in 2022 after disappointing results in a first-line study (AMEERA-5).

Roche is also in the race and gunning for a first-line indication with its giredestrant candidate, which was also held back by some disappointing mid-stage trial results, and is also testing it for adjuvant (post-surgery) use in earlier-stage breast cancer in the LIDERA trial, which the company reckons could allow for an all-comer label without the ESR1 mutation restriction.

AZ is also looking at adjuvant treatment with camizestrant in the CAMBRIA-1 and CAMBRIA-2 studies, as is Menarini with its ELEGANT trial, and is also running the SERENA-4 study that targets a broader first-line population of newly diagnosed HR-positive HER2-negative metastatic breast cancer with and without ESR1 mutations.

Lilly, meanwhile, is running the EMBER-3 trial of its candidate imlunestrant in the second-line setting – which generated mixed results earlier this year – and EMBER-4 as adjuvant therapy.

Another competitor is Arvinas/Pfizer, whose vepdegestrant is in a second-line study (VERITAC-2) and is also being tested in early-stage studies in combination with Pfizer's experimental CDK4 inhibitor atirmociclib in an all-comer, first-line population. And finally, Olema is running the second-line OPERA-1 trial of its hopeful palazestrant.

AZ previously reported results from the SERENA-2 study, which showed a median progression-free survival PFS) of six to eight months with camizestrant regardless of the ESR1 status and a benefit over oestrogen receptor blocker fulvestrant in head-to-head data.