AZD5363

Capivasertib

Capivasertib is a novel, highly potent, selective ATP-competitive pan-AKT kinase inhibitor that exerts similar activity against the three isoforms AKT1, AKT2 and AKT3. Positive data have emerged from early-phase trials, and several phase 3 trials are now underway. These phase 3 trials could provide the basis for regulatory approval of capivasertib in combination with fulvestrant as second or later-line treatment for metastatic HR-positive/HER2-negative breast cancer and in combination with paclitaxel as first-line treatment for locally advanced or metastatic triple-negative breast cancer.

About capivasertib

  1. AstraZeneca
  2. ATP-competitive pan-AKT kinase inhibitor
  3. Oral administration to treat triple-negative and HR-positive/HER2-negative breast cancer
  4. Also in late-phase trials for prostate cancer
  5. ~67,500 diagnosed incident cases of triple-negative breast cancer in women in the G7 markets in 2021
  6. ~460,500 diagnosed incident cases of HR-positive/HER-negative breast cancer in women in the G7 markets in 2021

Why is it a drug to watch?

Originating from a collaboration between AstraZeneca, Astex Pharmaceuticals Inc, the Institute of Cancer Research and Cancer Research Technology, capivasertib has shown promising results in early-phase trials, with clinical benefit to patients irrespective of their PIK3CA/AKT1/PTEN mutational status:

  1. PAKT: phase 2 of capivasertib plus paclitaxel demonstrated impressive progression-free survival (PFS) and overall survival (OS) over paclitaxel alone, as first-line therapy for metastatic triple-negative breast cancer.
  2. FAKTION: phase 1/2 of capivasertib plus fulvestrant demonstrated significantly increased PFS and OS over fulvestrant alone in inoperable locally advanced or metastatic ER-positive/HER2-negative breast cancer patients who had relapsed or progressed on an aromatase inhibitor.
  3. Multiple phase 3 trials are currently verifying and expanding on these results:
    • CAPItello-290: capivasertib plus paclitaxel as first-line treatment for inoperable locally advanced or metastatic triple-negative breast cancer
    • CAPItello-291: capivasertib plus fulvestrant in inoperable locally advanced or metastatic HR-positive/HER2-negative breast cancer patients who have relapsed or progressed on an aromatase inhibitor (i.e., second or later-line settings). Primary results from the trial showed that the combination of capivasertib plus fulvestrant significantly improved PFS over placebo plus fulvestrant, translating to a 40% reduction in the risk of disease progression or death in this population
    • CAPItello-292: capivasertib, palbociclib (IBRANCE®) and fulvestrant to treat inoperable locally advanced or metastatic HR-positive/HER2-negative breast cancer in patients who have relapsed within 12 months of completing endocrine adjuvant therapy or who have disease progression during the initial 12 months of first-line endocrine therapy for locally advanced unresectable or metastatic breast cancer (i.e., first and second-line settings). Primary results from the trial showed that the combination of capivasertib plus fulvestrant significantly improved PFS over placebo plus fulvestrant, translating to a 40% reduction in the risk of disease progression or death in this population.

Review and approval status

Expected launch:
2023: United States and Europe
2024: Japan

Patents estimated to expire beginning in 2028

How will capivasertib impact the market for breast cancer?

Owing to the large number of incident and recurrent cases, high treatment rates across the many lines of treatment in some patient segments, and typically long treatment durations, breast cancer is one of the largest therapy markets in oncology and is expected to grow from $22.6 billion in 2021 to $50.5 billion in 2031 in the G7 markets. Sales are expected to increase from $11.1 billion in 2021 to $27.7 billion in 2031 for HR-positive/HER2-negative breast cancer treatments and from $1.6 billion in 2021 to $6.8 billion in 2031 for triple-negative breast cancer treatments.

  1. Capivasertib is forecast to exceed sales of $1 billion in 2031 across the major G7 markets.
  2. Capivasertib is estimated to hold 5% of the first-line metastatic triple-negative breast cancer market and approximately 10% of the second, third and fourth-line metastatic HR-positive/HER2-negative breast cancer market in 2031 (across the G7 markets).
  3. Uptake of capivasertib will help sustain the growth of PI3K/AKT/mTOR pathway inhibitor sales in the midst of eroding everolimus sales due to generic options entering the market.

What gaps in treatment does capivasertib fill?

Triple-negative breast cancer is a particularly aggressive form of breast cancer characterized by a heterogeneous patient population with a lack of well-established predictive biomarkers. As such, targeted therapies are lacking as well as efficacious therapy options in general. For both metastatic HR-positive/HER-negative and triple-negative disease, capivasertib promises to advance and diversify treatment options for these difficult-to-treat patients.

What hurdles might it need to overcome to reach blockbuster status?

The market for triple-negative breast cancer treatments is expected to become increasingly competitive, with the booming drug development in this space owing to the high level of unmet need and lack of approved agents. Multiple drug classes are being investigated, including immune checkpoint inhibitors, antibody-drug conjugates, therapeutic vaccines, PARP inhibitors and CDK4/6 inhibitors. Since the majority of capivaserib’s sales are forecast to be derived from the metastatic HR-positive/HER2-negative setting, major hurdles in uptake and thus sales potential include competition from established earlier-to-market therapies in this setting and emerging novel therapies (e.g., oral selective estrogen receptor degraders [SERDs] and TROP2 inhibitors).

$0.53B
expected sales in 2027
90%
probability of success for capivasertib in the
United States for metastatic breast cancer.

Drug Timeline & Success Rates

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