On 16 November 2023, the FDA approved AstraZeneca’s (AZ) Truqap (capivasertib) in combination with Faslodex (fulvestrant) for patients with hormone receptor-positive (HR+), human epidermal growth factor receptor 2 negative (HER2-) locally advanced or metastatic breast cancer with one or more PIK3CA, AKT1 or PTEN (AKT pathway) mutations following progression after endocrine treatment either with or without CDK4/6 inhibitors in the metastatic setting or recurrence within 12 months of completing adjuvant therapy.

The approval was based on the CAPItello-291 trial (NCT04305496) where the median progression-free survival (PFS) for patients either with or without an AKT pathway mutation who received Truqap and fulvestrant was 7.2 months, compared to 3.6 months with fulvestrant and placebo (hazard ratio [HR]: 0.60; confidence interval [CI], 0.51 to 0.71; P<0.001). For patients with an AKT pathway mutation, the median PFS was 7.3 months in the experimental arm and 3.1 in the placebo arm (HR: 0.50; CI: 0.38 to 0.65; P<0.001).

The first line therapy for advanced HR+/HER2- breast cancer is CDK4/6 inhibitors such as Piqray (alpelisib) in combination with endocrine inhibitors; many of these patients develop resistance to the therapy combination and Truqap can help fill this unmet need. Alongside Truqap’s approval, the FDA approved a next-generation sequencing (NGS) diagnostic assay that detects these mutations, called FoundationOne CDx.

AZ originally hoped for approval for all HR+/HER- patients, but the FDA only approved Truqap for patients with AKT pathway mutations despite statistical significance in its primary endpoint in the wider patient population. This more limited approval was due to the smaller effect on PFS in the wider population and the unfavourable safety profile, with 13.0% of patients discontinuing treatment in the experimental arm of the trial compared to just 2.3% in the placebo arm. The most common adverse events in patients receiving Truqap were rash (in 12.1% patients vs. 0.3% of those receiving placebo) and diarrhoea (9.3% vs. 0.3%).

Around half of HR+/HER2- advanced breast cancer patients have one or more mutations in the AKT pathway. While this proportion is relatively high, it will still result in lower sales than AZ hoped for. However, 60% of HR+/HER2- advanced breast cancer patients already undergo an NGS assay to help determine treatment options, and this proportion is likely to increase as more biomarker-specific treatments are approved and therapies become more personalised.

While AZ did not gain a more inclusive first approval for Truqap, the future holds better possibilities. AZ is seeking Truqap’s approval as a first-line therapy in HR+/HER2- advanced breast cancer in combination with CDK4/6 inhibitors and fulvestrant; however, the primary endpoint of this trial is not expected until mid-2026 while the patent expires in 2030, leaving scant time to take advantage of the drug’s exclusivity. Truqap is also currently in Phase III trials for triple-negative breast cancer, with the readout expected in the first half of 2024, as well as HR-sensitive prostate cancer and metastatic castration-resistant prostate cancer. GlobalData’s Truqap analyst consensus forecast predicts sales volume to reach $662 million in 2029. In 2005, AZ paid Astex Therapeutics $5 million upfront and $270 million in milestone payments to license Truqap as well as other AKT candidates. Whether AZ’s licensing of this drug is a good deal or not remains to be seen.

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By GlobalData