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Page 4 of 22 Droste et al. J Cancer Metastasis Treat 2023;9:2 https://dx.doi.org/10.20517/2394-4722.2022.94

disproportionate censoring of patients with missing survival data between the two treatment arms and the
[22]
diversity of patients enrolled in the trial . A post hoc sensitivity analysis was performed to counteract the
effects of censoring by excluding patients with missing follow-up data. This operation resulted in a
prolonged median overall survival of 51.6 months in the palbociclib-letrozole-arm vs. 44.6 months in the
placebo-letrozole-arm [HR 0.869; confidence interval (CI) 0.706 to 1.069] .
[21]
Preliminary insights from subgroup analyses with balanced amounts of missing follow-up data were
presented at the American Society of Clinical Oncology Annual Meeting 2022 . They showed a benefit of
[23]
palbociclib plus letrozole for patients with an Eastern Cooperative Oncology Group performance status of 1
or 2 (HR 0.801), disease-free interval of more than 12 months (HR 0.728), prior endocrine therapy (HR
[23]
0.801), and bone-alone disease (HR 0.712) . Particularly outstanding was a median overall survival of 66.3
months for patients in the palbociclib-letrozole-arm with a disease-free interval of more than 12 months
and a proportion of 10% of patients who continued to receive palbociclib plus letrozole after a median
follow-up of 90 months . To date, the final publication of these results is pending. Nevertheless, based on
[21]
the available study results, the combination therapy of ribociclib plus endocrine therapy should be the
preferred treatment regimen.

In second-line therapy, adding all three CDK4/6 inhibitors significantly prolonged progression-free and
overall survival, as reported by the MONALEESA-3 trial for ribociclib, the MONARCH-2 trial for
abemaciclib, and the PALOMA-3 trial for palbociclib [Table 3] [15,21,24-26] . After a median follow-up of 44.8
months, the PALOMA-3 trial reported numerically longer overall survival for palbociclib plus fulvestrant
compared to fulvestrant alone; however, the difference in the overall study group was not significant . In
[24]
patients who had sensitivity to prior endocrine therapy, the addition of palbociclib resulted in significantly
longer overall survival (39.7 vs. 29.7 months; HR 0.72; CI: 0.55-0.94) . After an extended follow-up of 73.3
[24]
months, the improvement in overall survival in the palbociclib-fulvestrant-arm was statistically significant
[25]
in the entire study group .
Premenopausal women are treated like postmenopausal patients after adding a gonadotropin-releasing
hormone agonist like goserelin to suppress ovarian function or bilateral ovariectomy . The benefit of
[27]
adding ribociclib to endocrine therapy and goserelin was examined separately for premenopausal women in
the MONALEESA-7 trial [10,28] . The median progression-free survival was significantly prolonged to 23.8
months with ribociclib plus endocrine therapy compared to 13.0 months with endocrine therapy alone
(HR 0.55; P < 0.0001) . The recently published overall survival rates with an extended follow-up showed a
[10]
statistically significant benefit in median overall survival of 58.7 months with ribociclib vs. 48.0 months with
placebo (HR 0.76) . This survival benefit was generally consistent in subgroup analyses, including patients
[28]
[28]
younger than 40 years . The analysis of the premenopausal subgroup in the MONARCH-2 trial was
consistent with the improved progression-free and overall survival observed with abemaciclib plus
[29]
fulvestrant in the intent-to-treat population .
Side effect management is essential when using a CDK4/6 inhibitor to improve patient adherence. Table 4
briefly overviews the most common grade 3 or 4 adverse events for each CDK4/6 inhibitor. A meta-analysis
showed a significant increase in the rate of grade 3 and 4 adverse events with an addition of a CDK4/6
inhibitor to endocrine therapy compared to endocrine therapy alone, including neutropenia (HR 57.05;
[17]
P < 0.001), leukopenia (HR 36.36; P < 0.001), and diarrhea (HR 4.97; P < 0.001) . The choice of CDK4/6
inhibitor may also be based on the safety profile or dosing schedule. For example, the therapy with
abemaciclib is associated with fewer hematologic side effects than the other CDK4/6 inhibitors; however,