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Page 12 of 22 Droste et al. J Cancer Metastasis Treat 2023;9:2 https://dx.doi.org/10.20517/2394-4722.2022.94

[86]
support further development of sapanisertib using these dosing schedules .

PI3K inhibition
Approximately 40% of patients with HR-positive, HER2-negative breast cancer have activating mutations in
the gene encoding the alpha catalytic subunit of phosphatidylinositol-4,5-bisphosphate 3-kinase (PIK3CA),
resulting in hyperactivation of the alpha isoform of phosphatidylinositol 3-kinase (PI3Kα) [87,88] . Several
preclinical studies have demonstrated interactions between the ER and PI3K signaling pathways, as
inhibition of PI3K leads to the upregulation of ER signaling . In addition, PI3K inhibition enhances ER
[89]
function and dependence in HR-positive breast cancer [89,90] . First-generation PI3K inhibitors, also known as
pan-PI3K inhibitors, target all four isoforms of class I PI3K. The most studied pan-PI3K inhibitors for
breast cancer treatment are buparlisib and pictilisib [91,92] . Unselective inhibition of all PI3K isoforms is
accompanied by a high incidence of adverse events and leads to high treatment discontinuation rates, as
shown in Table 6. As a result, these pan-PI3K inhibitors were not further investigated in subsequent trials.
Over time, isoform-specific PI3K inhibitors emerged and opened new possibilities. The most important of
these so far is alpelisib, a PI3Kα-specific inhibitor. The SOLAR-1 trial investigated the efficacy of alpelisib in
patients with HR-positive, HER2-negative advanced breast cancer who had previously received endocrine
therapy . The phase III trial compared the combination therapy of alpelisib plus fulvestrant with placebo
[93]
plus fulvestrant. In the cohort of patients with PIK3CA-mutated cancer, a prolongation of progression-free
survival of 11.0 months was reported in the alpelisib-fulvestrant group compared to 5.7 months in the
control group (HR 0.65; P < 0.001) . A clinically relevant treatment benefit was not observed for alpelisib-
[93]
[93]
fulvestrant in the cohort without PIK3CA-mutated cancer . PIK3CA mutation testing does not necessarily
need to be performed on tumor tissue, as a preliminary analysis of ctDNA-based results showed similar
effects [93,94] . Alpelisib-related adverse events of grade 3 or 4 included hyperglycemia, diarrhea, or
maculopapular rash, and the percentage of patients that discontinued alpelisib due to adverse effects was
25% (compared to 4.2% in the placebo-fulvestrant-group) . The latter demonstrates the importance of
[93]
good adverse event management during alpelisib therapy. The final analysis of overall survival in the
SOLAR-1 trial did not reach the prespecified boundaries for statistical significance but showed a numerical
improvement of 39.3 months compared with 31.4 months when alpelisib vs. placebo was added to
[95]
fulvestrant (HR 0.86; P = 0.15) . To evaluate the clinical utility of alpelisib in the treatment algorithm of
breast cancer, the BYLieve trial was designed to investigate the efficacy of alpelisib in patients who had
experienced disease progression during or after treatment with a CDK4/6 inhibitor plus AI . The results
[96]
supported the clinical benefit of alpelisib following treatment with a CDK4/6 inhibitor [96,97] . This leads to the
conclusion that in case of disease progression during treatment with a CDK4/6 inhibitor plus endocrine
therapy, the patient should be evaluated for a PIK3CA mutation.

Recently, another intensively studied agent was the β-isoform-sparing pan-PI3K inhibitor taselisib. The
phase III SANDPIPER trial investigated the efficacy and safety of taselisib in combination with fulvestrant
[90]
in women with disease progression or recurrence during or after treatment with an AI . A statistically
significant but small prolongation of progression-free survival was reported in patients with PIK3CA-
mutant tumors in the taselisib-fulvestrant arm compared with the placebo-fulvestrant arm (7.4 months vs.
5.4 months; HR 0.70; P = 0.0037) . The proportion of patients who experienced adverse events of grade ≥ 3
[90]
was 49.5% in the taselisib-fulvestrant arm vs. 16.4% in the placebo-fulvestrant arm, with diarrhea and
hyperglycemia being the most frequently reported events . Serious adverse events occurred in as many as
[90]
[90]
32% of patients receiving taselisib (vs. 16.4% in the placebo arm) . In total, 16.8% of patients in the taselisib
[90]
arm discontinued treatment, compared with 8.9% in the placebo arm . Given the safety profile and modest
clinical benefit, the authors concluded that taselisib had no clinical benefit despite meeting the primary
endpoint .
[90]