Phase III clinical trial of AstraZeneca (AZN.US) breast cancer drug Etcamah may be thwarted, causing multi-billion dollar sales to be overshadowed

The Zhitong Finance App learned that AstraZeneca (AZN.US) announced on Friday that its SERENA-4 phase III trial for first-line treatment of ER-positive and HER2-negative advanced breast cancer with oral selective estrogen receptor (SERD) Etcamah (camizestrant) combined with pabosinib did not reach the main end. Although there was a numerical improvement in the patients' progression-free survival (PFS), it was not statistically significant.

Bloomberg Intelligence analyst John Murphy said that the failure of AstraZeneca's breast cancer drug trial could reduce sales by 2.6 billion to 3.8 billion US dollars in 2035. RBC Capital Markets analyst Trung Huynh previously estimated that the breast cancer drug's potential revenue was about 1 billion US dollars.

Despite this, after Roche Holdings' competitive experimental drug giredestrant failed to show benefits under similar circumstances, the market's expectations for the success of this indication were low. For Etcamah, the greater test will come from the results of several ongoing studies with a much larger patient population. However, some analysts did not include sales for this indication in their forecasts.

According to reports, traditional SERD fulvestrant (fulvestrant) can only be injected intramuscularly, and patients have poor compliance. Taking SERD orally once a day can theoretically replace aromatase inhibitors (AI) as a first-line standard endocrine therapy, and the market space is huge. However, the reality is that oral SERD combined with CDK4/6 inhibitors has never been able to outperform AI combined with CDK4/6 inhibitors in all frontline groups. AstraZeneca's Etcamah didn't do it, and Roche's Giredestrant didn't.

What's the problem? Perhaps AI itself is good enough. Among frontline people with positive ER and HER2 negative, PFS has been able to achieve more than 28 months. It is very difficult to significantly extend oral SERD on this basis. It may also be that the ER degradation efficiency of oral SERD is insufficient to show a differentiated advantage among the entire population. However, oral SERD is not entirely without opportunities; the key is population selection — patients with ESR1 mutations.

ESR1 mutations are an important mechanism for resistance to endocrine therapy in ER-positive breast cancer. About 30-40% of patients will experience ESR1 mutations during AI treatment. After the mutation, ER can continue to be activated in a low estrogen environment, driving tumor growth. Etcamah's Serena-6 trial was aimed at this group. 315 patients were randomly switched to Etcamah + CDK4/6 inhibitors or continued AI+ CDK4/6 inhibitors once detected through blood ctDNA testing every 2-3 months.

The results were tough: PFS 16.0 vs 9.2 months, HR 0.44, 56% lower risk of disease progression or death. PFS2 also improved significantly (25.7 vs 19.1 months, HR 0.63, p=0.00373). Based on this data, the FDA accelerated approval of etcamah in combination with CDK4/6 inhibitors on September 8 for HR-positive, HER2-negative locally advanced or metastatic breast cancer with ESR1 mutations during AI+CDK4/6 treatment. Many countries, including the European Union and Japan, have also approved it.

Susan Galbraith, AstraZeneca's Executive Vice President of Oncology Hematology R&D, made a clear statement after Serena-4's loss: “While we regret the SERENA-4 results, this further clarifies our focus — maximizing patient benefits based on SERENA-6 and reinforces the importance of ESR1 genetic testing in first-line treatments.”

The loss of SERENA-4 doesn't mean the end of Etcamah's story. What AstraZeneca is really betting on is adjuvant treatment for early-stage breast cancer. Two phase III trials, CAMBRIA-1 and CAMBRIA-2, plan to recruit approximately 10,000 patients with medium to high risk of recurrence in adjuvant treatment settings to evaluate the efficacy of Etcamah as a single agent, in combination with a CDK4/6 inhibitor, and after treatment with a CDK4/6 inhibitor. Cambria-1 compared ETCamAH extended adjuvant treatment for 5 years versus standard endocrine therapy, with medium to high risk of recurrence. Cambria-2 compared Upfront-assisted ETCamAH 7 years versus standard endocrine therapy, medium/high risk of recurrence. With a total of about 10,000 cases, the two trials are currently the largest development plan for oral SERD in early-stage breast cancer.

AstraZeneca's logic is that all people on the frontline cannot beat AI, but in early adjuvant treatment, the complete ER antagonism and degradation characteristics of oral SERD may be more thorough than AI, especially in people with a high risk of recurrence. If CAMBRIA is positive, ETCamah's market space will be far greater than that of people with advanced ESR1 mutations — this is also the core support for AstraZeneca's $5 billion peak sales forecast for Etcamah. However, CAMBRIA's data will not be read until 2027. Until then, etcamah could only be dosed slowly with the precise indication of ESR1 mutation.