ASCO 25: AZ pitches upfront oral SERD use in breast cancer

AstraZeneca wants to make its oral selective oestrogen receptor degrader (SERD) drug camizestrant a go-to frontline therapy for HR-positive breast cancer, and made its case at ASCO with data from the SERENA-6 trial.

The reveal of results first signposted earlier this year showed that camizestrant reduced the risk of disease progression or death by 56% in patients with advanced HR-positive breast cancer with ESR1 tumour mutations when used in combination with standard CDK4/6 inhibitor therapy.

SERENA-6 compared camizestrant alongside Pfizer's Ibrance (palbociclib), Novartis' Kisqali (ribociclib), or Eli Lilly's Verzenios (abemaciclib) to the CDK 4/6 inhibitors given with aromatase inhibitors like anastrozole or letrozole, currently the main first-line therapy for HR-positive breast cancer. Mutations in ESR1 are the most common mechanism of acquired resistance to that treatment regimen.

The new data – which has also been published in the New England Journal of Medicine – revealed that progression-free survival was 16 months among patients in the camizestrant group, compared to 9.2 months for those in the control arm.

Overall survival (OS) data showed a trend towards improvement, as did PFS2, an endpoint that measures the time from randomisation to the second disease progression or death from any cause, which some argue is more reliable than PFS as an indicator of clinical benefit.

According to AZ, SERENA-6 is also the first pivotal trial to show the value of measuring circulating tumour DNA (ctDNA) to detect ESR1 status and treat emerging resistance, although routine use of that testing would require a change in practice among oncologists that could hold back camizestrant's uptake – if approved for marketing.

That means that the ongoing SERENA-4 clinical trial of camizestrant in an all-comer HR-positive breast cancer population – with and without ESR1 mutations – is likely to be a more important study for AZ as it tries to position the SERD as a new first-line treatment option for the disease, and build towards peak sales it has modelled at $5 billion a year.

"Patients have an urgent need for new treatments that delay disease progression on first-line endocrine-based therapies," said François-Clément Bidard of the Institut Curie & UVSQ/Université Paris-Saclay, one of the study's principal investigators.

The results suggest that the use of an oral SERD in place of aromatase inhibitors after the emergence of an ESR1 mutation "delays progression of disease and extends the benefit of 1st-line treatment, representing an important step forward for patients, and a potential shift in clinical practice."

At the moment, the only oral SERD that has reached the market so far is Menarini and Stemline's Orserdu (elacestrant), which was cleared as a second-line therapy for HR-positive advanced breast cancer with ESR1 mutations in 2023.

Vepdegestrant extends PFS when used second-line

At ASCO, Arvinas and Pfizer revealed its oral SERD vepdegestrant could become a potential rival to Orserdu after reporting data from the VERITAC-2 trial that showed it was more effective than fulvestrant in the second-line setting, although the data raised as many questions as it answered.

VERITAC-2 is the first pivotal trial of a PROTAC (proteolysis-targeting chimaera), although the release of the top-line results earlier this year generated disappointment as it showed an improvement in PFS for the ESR1-mutated population only, and not the overall, all-comer cohort.

The look at the full data at ASCO has done little to dispel that, with a median PFS of 5 months for vepdegestrant and 2.1 months for fulvestrant, an injectable SERD, and no difference in the entire group.

Pfizer and Arvinas have said they intend to file for approval on the back of the data. However, the impression at the moment is there will not be much to differentiate their drug from Orserdu and another oral SERD, Eli Lilly's imlunestrant, which has also been submitted for FDA approval in combination with CDK 4/6 inhibitors for use as a second-line treatment for ESR1-mutated, HR-positive breast cancer.

Photo by Sawyer Bengtson on Unsplash