FDA's ODAC delivers one loss, one win for AstraZeneca

In its first meeting for months, the FDA's Oncologic Drugs Advisory Committee (ODAC) voted against AstraZeneca's oral selective oestrogen receptor degrader (SERD) drug camizestrant.

By a margin of six votes to three, the panel concluded that the results of the SERENA-6 trial of camizestrant did not support use of camizestrant in combination with CDK inhibitors – Pfizer's Ibrance (palbociclib), Novartis' Kisqali (ribociclib), or Eli Lilly's Verzenios (abemaciclib) – as a first-line treatment for HR-positive, HER2-negative breast cancer with ESR1 mutations.

AZ had proposed a biomarker-based approach to treatment that involved measuring circulating tumour DNA (ctDNA) to detect ESR1 mutations – which point to the emergence of resistance to treatment – and switching patients from their current therapy to its oral SERD.

According to SERENA-6 data reported at last year's ASCO congress, that approach reduced the risk of disease progression or death by 56% compared to the CDK 4/6 inhibitors given in combination with an aromatase inhibitor. Mutations in ESR1 are the most common mechanism of acquired resistance to that treatment regimen.

The sticking point for panellists appeared to be that the improvement in progression-free survival (PFS) was not accompanied by a statistically significant gain in overall survival (OS), which is considered a more rigorous outcome measure. Some panellists suggested that an OS benefit should be seen before approval, given that AZ is proposing a step-change in established clinical practice for these patients.

That view was also laid out in the FDA review document (PDF), which suggested that there is not sufficient evidence from SERENA-6 to show the clinical benefit from a strategy in which patients receive camizestrant at ESR1 mutation detection, rather than at radiographic progression as at present.

"We are disappointed with the mixed outcome of today's ODAC meeting," said Susan Galbraith, AZ's head of oncology and haematology R&D.

"We strongly believe in the results of the SERENA-6 trial, and are encouraged that the committee saw camizestrant as a safe and effective potential new medicine," she added. "We remain confident in the clinical benefit the combination can bring to patients by changing therapeutic strategy at the earliest opportunity."

The company may have an opportunity to make its case when additional results from SERENA-6 are presented at this year's ASCO congress, which will start later this month in Chicago. Meanwhile, regulatory applications for camizestrant in this setting are also under review in the EU, Japan, and several other countries.

The FDA does not have to abide by the advice of the ODAC, but the vote suggests 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 crucial for AZ as it tries to position the SERD as a new first-line treatment option for the disease – and build toward peak sales it has modelled at $5 billion a year. SERENA-4 data is due to read out in the latter half of this year.

There are currently two marketed drugs in the oral SERD class – Menarini/Stemline's Orserdu (elacestrant) and Eli Lilly's Inluriyo (imlunestrant) – which are both approved for second-line treatment of HR+, HER- breast cancer with ESR1 mutations.

Truqap backed for prostate cancer

The ODAC delivered better news for AZ with a seven-to-one vote in favour of its AKT inhibitor Truqap (capivasertib) in combination with Johnson & Johnson's Zytiga (abiraterone) and androgen deprivation therapy (ADT) for PTEN-deficient metastatic hormone-sensitive prostate cancer (mHSPC).

This form of prostate cancer is known to be aggressive, progressing quickly to more advanced disease, and has limited treatment options. Estimates for the frequency of PTEN mutations in prostate cancer vary widely, between around 15% and 60%, depending on the type and stage of the disease, but testing for the biomarker isn't widespread at the moment.

Truqap is already approved for relapsed or refractory HR+/HER2- advanced breast cancer, but AZ's efforts to expand its use into other indications like triple-negative breast cancer have so far been unsuccessful.

The mHSPC filing is based on the results of the CAPItello-281 study, which showed that Truqap achieved a statistically significant 19% reduction in the risk of radiographic disease progression or death compared to placebo.