Olaparib Combo May Show Clinical Benefit in Advanced HER2+ Breast Cancer

The OPHELIA trial assessed the efficacy and safety of olaparib plus trastuzumab in HER2-positive advanced breast cancer with germinal BRCA mutations.

Olaparib (Lynparza), a PARP inhibitor, in combination with trastuzumab (Herceptin), met the primary end point for clinical benefit rate (CBR) in a small cohort of patients with HER2-positive advanced breast cancer with germinal BRCA mutations who had received at least 1 prior systemic therapy, according to findings from the phase 2 OPHELIA trial (NCT03931551) published in The Breast.

Investigators found that the CBR was 80% (n = 4/5; 95% CI, 28.4%-99.5%, P < .001); objective response rate (ORR) was 60% (95% CI, 14.7%-94.7%), with 1 complete response and 2 partial responses observed. Additionally, most adverse events (AEs) were lower than grade 3, and no treatment-related deaths were observed. No new safety signals were identified.

“This study was terminated prematurely because of slow accrual. However, despite not reaching the expected enrollment, the primary endpoint was met, according to the statistical plan,” wrote José Enrique Alés-Martínez, MD, PhD, former director of clinical research at Centro de Patología de la Mama-Fundación Tejerina, with study coauthors. “Recruitment was challenging for 2 reasons. First, the population evaluated is rare….Second, patients with HER2-positive [advanced breast cancer] are often not tested for [germinal BRCA mutations] in the absence of a suggestive family history. Thus, patients with HER2-positive [advanced breast cancer] and [germinal BRCA mutations]could have been historically underdiagnosed.”

Investigators in the single-arm, open-label, multicenter phase 2 OPHELIA identified 5 patients with HER2-positive advanced breast cancer and previously known germinal BRCA mutations. Additionally, 63 other patients with HER2 status had germinal BRCA mutationstatus analyzed, but none were included for analysis: 61 (96.8%) due to a lack of germinal BRCA mutationsstatus, 1 died prior to enrollment, and 1 was not included because of the OPHELIA trial ending prematurely.

Patients were dosed with 300 mg of olaparib twice daily plus 600 mg of subcutaneous trastuzumab or a loading dose of 8 mg/kg followed by 6 mg/kg on day 1 of each 3-week cycle. Treatment continued until unacceptable toxicity, progressive disease, or withdrawal of consent.

CT or MRI were conducted at 6-week intervals up to week 24, and every 12 weeks following for the chest, abdomen, and pelvis. If bone involvement was found at baseline, bone scans were then repeated every 24 weeks during the study.

The primary end point of the study was CBR, defined as the rate of patients achieving overall tumor response or stable disease for 24 or more weeks. Secondary end points included ORR, time to response (TTR), duration of response (DOR), progression-free survival (PFS), overall survival (OS), and safety.

As of data cut-off, 2 patients continued to receive treatment for 11.7 and 19.9 months. The remaining 3 discontinued treatment due to grade 3 AEs (n = 1) or disease progression (n = 2). Median duration of treatment of olaparib was 23.6 weeks (range, 6-83.3).

Median duration of follow-up was 18.7 months (range, 11.7-22.1). Median TTR and median DOR was 2.9 months (range, 1.2-16.5) and 3.8 months (range, 2.5-8.3), respectively.

PFS events occurred in 2 patients at 5.2 and 1.2 months, respectively. At 14.4 and 18.7 months, respectively, these patients died during the follow-up period.

Any-grade and grade 3 AEs were reported in 100% and 20% of patients, respectively. Notably, at least 1 patient experienced a hematologic grade 3 AE, including 1 instance each of blood and lymphatic system disorders, anemia, lymphopenia, leukopenia, and neutropenia––a single grade 3 instance of pericardial effusion occurred as well. Common any-grade AEs occurring in 2 or more patients include blood and lymphatic disorders (n = 2), anemia (n = 2), lymphopenia (n = 2), gastrointestinal disorders (n = 4), nausea (n = 3), vomiting (n = 2), fatigue (n = 3), and back pain (n = 2).

Reference

Alés-Martínez JE, Balmaña J, Sánchez-Rovira P, et al. Olaparib plus trastuzumab in HER2-positive advanced breast cancer patients with germline BRCA1/2 mutations: the OPHELIA phase 2 study. Breast. 2024;77:103780. doi:10.1016/j.breast.2024.103780