On 24 May, the US Food and Drug Administration (FDA) approved Piqray (alpelisib), a first-in-class phosphoinositide 3-kinase (PI3K) inhibitor for use in combination with fulvestrant as a treatment for postmenopausal women with hormone receptor-positive (HR+), PI3KCA-mutated metastatic breast cancer following progression on endocrine-based therapy.

Metastatic breast cancer 2019

The FDA also approved a companion diagnostic to detect PI3KCA mutation in a tissue and/or liquid biopsy. The approval was based on data from the Phase III SOLAR-1 trial demonstrating an improvement in progression-free survival (PFS) in patients harbouring PI3KCA mutations by 11.0 months compared with 5.7 months in patients who received placebo + fulvestrant.

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The strong rationale for targeting this pathway is based on the prevalence of oncogenic alterations, which are present in approximately 40–50% of HR+ metastatic breast cancer. Despite the clear involvement of the pathway in breast carcinogenesis, there have been several notable failures at targeting it, including Adlai Noryte’s buparlisib and Roche’s taselisib, both of which had modest efficacy but were accompanied by an unacceptable safety profile.

The long-awaited approval of a PI3K inhibitor resulted from several refinements in the strategy, specifically targeting the α isoform of the protein, and the development of protein kinase B (Akt) inhibitors, such as ipatasertib and capivasertib, which target the component downstream of the PI3K protein.

Clinicians interviewed by GlobalData expect that the approval of Piqray will provide a new standard of care for patients who harbour a PI3KCA mutation and have progressed on prior endocrine therapy. Piqray’s approval represents a commercial success for Novartis, especially considering the therapy’s first-to-market status and the relatively large market size that it will monopolize until the anticipated launches of competitors in 2021.

Furthermore, there is a clear clinical need for drugs used to treat patients who are endocrine refractory. Consequently, Piqray occupies a strong position in the metastatic setting for patients harbouring a PI3KCA mutation, and competitors will seek to enhance commercial success by carving out a therapeutic niche in the treatment paradigm for HR+ disease.

AstraZeneca’s capivasertib and Roche’s ipatasertib are hoping to achieve good market penetration due to the fact that efficacy in early phase clinical trials is seen regardless of PI3K activation status. In an increasingly dynamic and exciting time for clinical development, the PI3K/Akt space provides yet another opportunity to reshape the treatment of patients with HR+ breast cancer.