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Page 14 of 22 Droste et al. J Cancer Metastasis Treat 2023;9:2 https://dx.doi.org/10.20517/2394-4722.2022.94

studies and demonstrated antitumor activity [107-110] . The efficacy of capivasertib in combination with
fulvestrant was tested in patients with PTEN-mutant HR-positive metastatic breast cancer in a phase I
[108]
multipart expansion study by Smyth et al. . The results showed a clinical benefit rate 17% in fulvestrant-
naive and 42% in fulvestrant-pretreated patients after 24 weeks and an objective response rate of 8% vs.
21% . Co-mutations occurred in PIK3CA, ESR1, and TP53, with a clonal dominance of PTEN in most
[108]
[108]
patients . In conclusion, the study reported the efficacy and antitumor activity of capivasertib plus
fulvestrant with an acceptable safety profile in this heavily pretreated cohort . The results showed slightly
[108]
better efficacy in fulvestrant-pretreated patients, but notable phenotypic and genomic differences were
observed between the cohorts .
[108]
The FAKTION trial is another study evaluating the AKT kinase inhibitor capivasertib. The phase II study
investigated the effect of adding capivasertib to fulvestrant on progression-free survival in patients with AI-
resistant advanced breast cancer . Median progression-free survival was significantly longer in the
[109]
capivasertib plus fulvestrant group than in the placebo-fulvestrant group (10.3 vs. 4.8 months; HR 0.58;
P = 0.0044) . Furthermore, adding capivasertib significantly prolonged overall survival to 29.3 months
[109]
compared to 23.4 months in the placebo group (HR 0.66; two-sided P = 0.035) . A second analysis was
[111]
performed with patients identified as expanded PI3K/AKT/PTEN pathway-altered subgroup by an
expanded biomarker panel. Survival rates in this specific subgroup showed even better results: Median
progression-free survival was 12.8 months in the capivasertib arm vs. 4.6 months in the placebo arm
(HR 0.44; P = 0.0014). Furthermore, median overall survival was 38.9 months with capivasertib plus
[111]
fulvestrant vs. 20.0 months in the placebo arm (HR 0.46; P = 0.0047) . In comparison, there was no
statistical significance in survival rates between the treatment arms in the expanded pathway non-altered
subgroup . Adverse events such as hypertension, diarrhea, and fatigue were more common with
[111]
capivasertib, and serious adverse events occurred only in the capivasertib arm . These results once again
[109]
highlight the utility of biomarker testing. Currently, the efficacy of capivasertib plus fulvestrant is being
further evaluated by the phase III CAPItello-291 trial. The results of this trial will not only provide further
insights into the efficacy of capivasertib but also demonstrate the efficacy in patients previously treated with
a CDK4/6 inhibitor, as the latter was an exclusion criterion in the FAKTION trial.

Pathogenic variants in DNA-repair-related genes
In addition to identifying mechanisms leading to acquired endocrine resistance, the detection of germline
mutations has become a mainstay of individualized tumor therapy. It is increasingly becoming possible to
perform comprehensive genomic tumor profiling using a variety of multigene assays that allow the
detection of potentially treatable genetic alterations . In unselected populations of breast cancer patients,
[112]
approximately five percent carry a germline BReast CAncer (BRCA) gene mutation [113,114] . A mutation in the
BRCA 1 gene is known to predispose to triple-negative breast cancer, while patients with BRCA 2 mutation
are most likely to develop HR-positive breast cancer [115,116] . Germline testing of patients with HER2-negative
metastatic breast cancer for a BRCA 1/2 mutation as a predictive biomarker for the efficacy of
poly(adenosine diphosphate-ribose) polymerase (PARP) inhibition is now part of the mandatory diagnostic
workup in metastatic breast cancer. PARP inhibitors were initially used in treating ovarian cancer, where
PARP inhibition has become an integral part of the treatment algorithm [117-119] . Recently, PARP inhibition
has also been shown to have a promising effect and clinically meaningful benefit in patients with metastatic
breast cancer and germline BRCA mutation [120-123] . In the OlympiAD trial, olaparib monotherapy provided a
significant benefit over standard therapy in patients with HER2-negative metastatic breast cancer who had
not received more than two prior chemotherapy regimens for metastatic disease . Median progression-
[120]
free survival was significantly longer (7.0 months vs. 4.2 months; P < 0.001), and the response rate was
significantly higher (59.9% vs. 28.8%) compared to the standard therapy group . At the same time, fewer
[120]
high-grade adverse events were observed with olaparib monotherapy, resulting in a lower treatment