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Optimizing Tx of HRpos HER2neg MBC

CME

Optimizing Treatment for Patients With HR-Positive/HER2-Negative MBC

Physicians: Maximum of 0.50 AMA PRA Category 1 Credit™

Released: March 24, 2025

Expiration: September 23, 2025

Sara A. Hurvitz
Sara A. Hurvitz, MD, FACP
CME/CE Information

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RIGHT Choice: Ribociclib + ET vs Chemotherapy for HR+/HER2- ABC

Several randomized trials have also investigated the efficacy and safety of a CDK4/6 inhibitor–based treatment vs a chemotherapy-based approach in the first-line treatment of patients with HR-positive, HER2-negative advanced breast cancer. The randomized phase II RIGHT Choice trial evaluated investigator’s choice of combination chemotherapy vs ribociclib in combination with an NSAI (anastrozole or letrozole) and ovarian suppression for 222 pre- or perimenopausal women with high-risk HR-positive, HER2-negative advanced breast cancer who had not previously received chemotherapy or ET for advanced disease (NCT03839823). The primary endpoint was PFS by local review, and the secondary endpoints included time to treatment failure (TTF), response, safety, and quality of life measures.

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RIGHT Choice: PFS and OS Outcomes

After a median follow-up of 37 months, the median PFS was significantly prolonged with ribociclib plus an NSAI and ovarian suppression (21.8 months) vs combination chemotherapy (12.8 months) with a 9-month improvement (HR: 0.611; 95% CI: 0.429-0.870; P = .003).27 Of note, however, there was no significant difference in OS between the treatment arms (HR: 0.921; 95% CI: 0.560-1.516).

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RIGHT Choice: AEs

As previously stated, neutropenia is the most common AE associated with ribociclib; it was reported in 83.9% of patients on the ribociclib arm compared with 50% of those who received combination chemotherapy. Grade 3 or higher neutropenia was reported in 59.8% of patients who received ribociclib compared with 36% of those who received combination chemotherapy. That said, the rates of any grade increased ALT/AST, nausea, alopecia, vomiting, diarrhea and fatigue were lower on the ribociclib arm compared with the combination chemotherapy arm.

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PADMA: Palbociclib + ET vs Chemotherapy for HR+/HER2- MBC

PADMA is a prospective, randomized phase IV trial that evaluated the efficacy and safety of ET plus palbociclib compared with physician's choice chemotherapy with or without ET as maintenance (NCT03355157). This study is important because it interrogated whether patients with higher-risk HR-positive, HER2-negative MBC fare better when treated with a chemotherapy-based approach in the front-line advanced disease setting. The study excluded patients with asymptomatic bone-only oligometastases. A total of 150 patients were enrolled on the trial. The primary endpoint was TTF, and the secondary endpoints included PFS, OS, safety, tolerability, and treatment compliance.

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PADMA: TTF Outcome 

The results from the PADMA trial were presented at the 2024 breast cancer annual meeting.28 After a median follow-up of 36.8 months, the median TTF was significantly prolonged with palbociclib plus ET (17.2 months) compared with chemotherapy (6.1 months). Of note, the median TTF with the addition of palbociclib to ET was almost 3 times better than that with chemotherapy (HR: 0.46; 95% CI: 0.31-0.69; P <.001).

Subgroup analysis of TTF consistently showed improved benefit with palbociclib plus ET vs chemotherapy. The TTF benefit was consistent regardless of the presence or absence of symptoms, liver involvement, and M0/M1 disease. These results underscore the fact that chemotherapy, although generally more toxic than CDK4/6 inhibitors, is not necessarily the better first-line treatment for patients with HR-positive, HER2-negative MBC, even when the disease is symptomatic or involves organs.

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PADMA: PFS and OS Outcomes

Similar to the TTF results, there was a statistically significant improvement in PFS with the addition of palbociclib to ET. The median PFS was 18.7 months with palbociclib plus ET compared with 7.8 months with chemotherapy (HR: 0.45; 95% CI: 0.29-0.70; P <.001). With regard to OS, there was a numeric trend for improvement with palbociclib plus ET (46.1 months) compared with chemotherapy (36.8 months).

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PADMA: Safety Summary

Although the rate of any hematologic treatment-related adverse event (TRAE) was higher with palbociclib plus ET (96.8%) vs chemotherapy (58.6%), this difference was primarily due to the high rates of neutropenia associated with palbociclib compared with chemotherapy (P <.001). It is important to note that palbociclib-associated neutropenia is usually asymptomatic. In contrast, the rates of any grade nonhematologic TRAEs reported on either of the treatment arms were similar (82.3% vs 93.1%).

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