Endocrine therapy and cyclin-dependent kinase (CDK) inhibitor therapy

The monarchE trial (NCT03155997) examined the effect of adding abemaciclib to standard endocrine therapy in women with HER2-negative hormone receptor–positive breast cancer who were at high risk of recurrence.[89] The trial enrolled 5,637 women who met one of the following criteria: four or more positive nodes; or one to three positive nodes and either tumor size 5 cm or larger, histological grade 3, or central Ki67 20% or greater. The women were randomly assigned in a 1:1 ratio to standard-of-care adjuvant endocrine therapy with or without open-label abemaciclib (150 mg twice daily for 2 years). The primary end point was IDFS and secondary end points included DRFS, OS, and safety.

The monarchE trial (NCT03155997) examined the effect of adding abemaciclib to standard endocrine therapy in women with HER2-negative hormone receptor–positive breast cancer who were at high risk of recurrence.[89] The trial enrolled 5,637 women who met one of the following criteria: four or more positive nodes; or one to three positive nodes and either tumor size 5 cm or larger, histological grade 3, or central Ki67 20% or greater. The women were randomly assigned in a 1:1 ratio to standard-of-care adjuvant endocrine therapy with or without open-label abemaciclib (150 mg twice daily for 2 years). The primary end point was IDFS and secondary end points included DRFS, OS, and safety.

At a median follow-up of 54 months, an analysis showed that adding abemaciclib resulted in a substantial improvement in IDFS (5-year IDFS: 76% vs. 83.6%; HR, 0.680; 95% CI, 0.599–0.772; P < .001) and DRFS (5-year DRFS: 79.2% vs. 86%; HR, 0.675; 95% CI, 0.588–0.774; P < .001).

The monarchE trial (NCT03155997) examined the effect of adding abemaciclib to standard endocrine therapy in women with HER2-negative hormone receptor–positive breast cancer who were at high risk of recurrence.[89] The trial enrolled 5,637 women who met one of the following criteria: four or more positive nodes; or one to three positive nodes and either tumor size 5 cm or larger, histological grade 3, or central Ki67 20% or greater. The women were randomly assigned in a 1:1 ratio to standard-of-care adjuvant endocrine therapy with or without open-label abemaciclib (150 mg twice daily for 2 years). The primary end point was IDFS and secondary end points included DRFS, OS, and safety.

There were 208 deaths in the abemaciclib arm and 234 deaths in the endocrine therapy-alone arm. This difference was not statistically significant.[90][Level of evidence B1]

The monarchE trial (NCT03155997) examined the effect of adding abemaciclib to standard endocrine therapy in women with HER2-negative hormone receptor–positive breast cancer who were at high risk of recurrence.[89] The trial enrolled 5,637 women who met one of the following criteria: four or more positive nodes; or one to three positive nodes and either tumor size 5 cm or larger, histological grade 3, or central Ki67 20% or greater. The women were randomly assigned in a 1:1 ratio to standard-of-care adjuvant endocrine therapy with or without open-label abemaciclib (150 mg twice daily for 2 years). The primary end point was IDFS and secondary end points included DRFS, OS, and safety.

Because of adverse events, abemaciclib dose adjustments occurred in 1,901 patients (68.1%); 56.9% of these patients had dose omissions and 41.2% had dose reductions. In the abemaciclib arm, 463 patients (16.6%) discontinued abemaciclib because of adverse events, 306 of whom remained on endocrine therapy.[89]

The monarchE trial (NCT03155997) examined the effect of adding abemaciclib to standard endocrine therapy in women with HER2-negative hormone receptor–positive breast cancer who were at high risk of recurrence.[89] The trial enrolled 5,637 women who met one of the following criteria: four or more positive nodes; or one to three positive nodes and either tumor size 5 cm or larger, histological grade 3, or central Ki67 20% or greater. The women were randomly assigned in a 1:1 ratio to standard-of-care adjuvant endocrine therapy with or without open-label abemaciclib (150 mg twice daily for 2 years). The primary end point was IDFS and secondary end points included DRFS, OS, and safety.

Similar results were found in a prespecified subgroup analysis of patients who had received neoadjuvant chemotherapy and had residual disease after surgery.[91]

The NATALEE trial (NCT03701334) evaluated adding ribociclib to standard adjuvant therapy in women and men with stage II to stage III HER2-negative hormone receptor–positive breast cancer.[92] A total of 5,101 patients were randomly assigned without blinding to receive either a nonsteroidal AI alone or in combination with ribociclib within 12 months of starting a nonsteroidal AI. The primary end point was IDFS.

The NATALEE trial (NCT03701334) evaluated adding ribociclib to standard adjuvant therapy in women and men with stage II to stage III HER2-negative hormone receptor–positive breast cancer.[92] A total of 5,101 patients were randomly assigned without blinding to receive either a nonsteroidal AI alone or in combination with ribociclib within 12 months of starting a nonsteroidal AI. The primary end point was IDFS.

At the time of the second planned interim analysis, when the median duration of follow-up was 28 months, there was a significant difference in IDFS favoring the ribociclib arm (3-year IDFS, 90.4% for ribociclib plus nonsteroidal AI vs 87.1% for nonsteroidal AI alone) (HR, 0.75; 95% CI, 0.62–0.91; P = .003). This P-value exceeded the prespecified cutoff of .0256.[92][Level of evidence B1]

The NATALEE trial (NCT03701334) evaluated adding ribociclib to standard adjuvant therapy in women and men with stage II to stage III HER2-negative hormone receptor–positive breast cancer.[92] A total of 5,101 patients were randomly assigned without blinding to receive either a nonsteroidal AI alone or in combination with ribociclib within 12 months of starting a nonsteroidal AI. The primary end point was IDFS.

The exploratory end points of distant DFS, RFS, DRFS, and OS favored the ribociclib arm, but the differences were not formally tested for significance in this analysis.

The NATALEE trial (NCT03701334) evaluated adding ribociclib to standard adjuvant therapy in women and men with stage II to stage III HER2-negative hormone receptor–positive breast cancer.[92] A total of 5,101 patients were randomly assigned without blinding to receive either a nonsteroidal AI alone or in combination with ribociclib within 12 months of starting a nonsteroidal AI. The primary end point was IDFS.

Neutropenia (62.15% vs. 4.5%) and liver-related events (25.4% vs. 10.6%) were more common in the ribociclib-plus-nonsteroidal AI group than the nonsteroidal AI-alone group. A total of 477 patients discontinued ribociclib, and 554 patients had dose reductions. There were no treatment-related deaths.

The PALLAS trial (NCT02513394) studied the effect of adding palbociclib to standard adjuvant therapy in women with stage II to stage III HER2-negative hormone receptor–positive breast cancer.[93] In the trial, 5,760 women who were within 6 months of initiating adjuvant endocrine therapy were randomly assigned in a 1:1 ratio without blinding to receive palbociclib plus endocrine therapy or to continue endocrine therapy alone. The primary end point was IDFS.

The PALLAS trial (NCT02513394) studied the effect of adding palbociclib to standard adjuvant therapy in women with stage II to stage III HER2-negative hormone receptor–positive breast cancer.[93] In the trial, 5,760 women who were within 6 months of initiating adjuvant endocrine therapy were randomly assigned in a 1:1 ratio without blinding to receive palbociclib plus endocrine therapy or to continue endocrine therapy alone. The primary end point was IDFS.

At the time of the second interim analysis, no significant difference between the treatment arms was found (HR, 0.93; 95% CI, 0.76–1.15; 3-year IDFS rates, 88.2% vs. 88.5%; P = .51).[93][Level of evidence B1] The planned final analysis yielded similar results.[94]

The PALLAS trial (NCT02513394) studied the effect of adding palbociclib to standard adjuvant therapy in women with stage II to stage III HER2-negative hormone receptor–positive breast cancer.[93] In the trial, 5,760 women who were within 6 months of initiating adjuvant endocrine therapy were randomly assigned in a 1:1 ratio without blinding to receive palbociclib plus endocrine therapy or to continue endocrine therapy alone. The primary end point was IDFS.

As the test statistic for futility crossed the prespecified boundary, the data safety monitoring committee recommended that patients discontinue palbociclib therapy.

The PALLAS trial (NCT02513394) studied the effect of adding palbociclib to standard adjuvant therapy in women with stage II to stage III HER2-negative hormone receptor–positive breast cancer.[93] In the trial, 5,760 women who were within 6 months of initiating adjuvant endocrine therapy were randomly assigned in a 1:1 ratio without blinding to receive palbociclib plus endocrine therapy or to continue endocrine therapy alone. The primary end point was IDFS.

Neutropenia and leukopenia were much more common in patients on the palbociclib arm, and fatigue was slightly more common. There were no treatment-related deaths.