ASCO26: After negative adcomm, AZ builds case for oral SERD

AstraZeneca has presented new data from the SERENA-6 trial of camizestrant in advanced breast cancer that it hopes will persuade the FDA to approve the oral selective oestrogen receptor degrader (SERD) – even though the agency's experts advised against doing so.

AZ is hoping to position camizestrant as a frontline treatment for locally advanced or metastatic HR-positive, HER2-negative breast cancer with a mutation in the ESR1 gene, and with SERENA-6 is making the case to switch to its drug from an aromatase inhibitor (anastrozole or letrozole), both given in combination with a CDK4/6 inhibitor.

In an update to trial results first reported at last year's ASCO, the camizestrant combination reduced the risk of disease progression or death by 55% compared to the control treatment, with median progression-free survival (PFS) of 16.8 months versus 9.2 months, respectively.

There was also a 37% reduction in the risk of a second progression (PFS2), which AZ said showed that the benefit of switching was "sustained beyond initial progression [and] maintained even after patients received subsequent therapies."

After the FDA's Oncologic Drugs Advisory Committee (ODAC) voted that camizestrant's data did not support approval in April, the FDA has extended its review of the drug so it can take a look at data on ESR1 mutations in circulating tumour DNA (ctDNA), specifically how well ctDNA clearance data align with efficacy outcomes.

At ASCO, co-principal investigator François-Clément Bidard of Institut Curie & Versailles University in France reported that switching to camizestrant led to a 99% median reduction in total ctDNA, while patients who remained on standard of care saw a 64% increase.

Moreover, 51% of patients receiving the camizestrant combination achieved total ctDNA clearance compared to just 1.9% in the control group. An exploratory analysis from SERENA-6 showed that total ctDNA clearance was associated with overall survival benefit, with a hazard ratio of 0.39.

Overall, there was a trend towards improved OS in the study, with a hazard ratio of 0.87, and this will be monitored to see if it becomes statistically significant with further follow-up. And AZ's drug delayed the need for more intensive subsequent treatment, including chemotherapy or antibody-drug conjugates (ADCs), by around four months.

"Optimising outcomes for patients with HR-positive advanced breast cancer early in their treatment is critical because once the disease progresses, it becomes harder to treat and outcomes worsen," commented Bidard.

"The updated SERENA-6 results support the paradigm of switching to a camizestrant-based combination in the first-line setting upon emergence of an ESR1 mutation and demonstrate durable improvements beyond initial treatment," he added.

The ODAC vote was viewed as a major setback in AZ's plan to grow camizestrant into a $5 billion-a-year drug, part of a portfolio of new medicines it hopes will drive sales above the $80 billion threshold by the end of the decade, and the company will be hoping the new data will get the FDA's review back on track.

Camizestrant has already been approved in the United Arab Emirates and Saudi Arabia based on the SERENA-6 data, and recommended for approval in the EU, with additional filings in Japan and other countries ongoing.