PARP inhibitors have shown activity in multiple cancers that are associated with BRCA mutations. AstraZeneca’s Lynparza (olaparib), one such PARP inhibitor, is indicated for various advanced cancer types. While Lynparza, in 2017, was approved to treat patients with germline BRCA-mutated (gBRCAm), HER2-negative metastatic breast cancer previously treated with chemotherapy in the neoadjuvant, adjuvant, or metastatic setting, it is still not approved for use in high-risk HER2 negative early breast cancer with gBRCAm.
OlympiA study is evaluating Lynparza in patients with gBRCA1/2 mutated HER2 negative early breast cancer who have completed definitive local treatment and neoadjuvant or adjuvant chemotherapy. It is a randomized, double-blind, parallel-group, placebo-controlled multicenter Phase III trial, which, once complete, can provide Lynparza with the commercial opportunity in the adjuvant setting. Of note, AstraZeneca and Merck Sharp & Dohme (MSD) will present the positive results from the international Phase III OlympiA trial at ASCO 2021 (Abstract LBA1).
Earlier this year, the Independent Data Monitoring Committee (IDMC), based on the planned interim analysis, concluded that Lynparza crossed the superiority boundary for its primary end point of invasive disease-free survival (iDFS) as adjuvant therapy in high-risk gBRCAm HER2-negative early-stage breast cancer over placebo. As per MSD “Analysis of the OlympiA trial, based upon the IDMC recommendation, could represent a potential step forward for patients with early-stage, high-risk primary breast cancer with a germline BRCA mutation”. Thus, the successful attainment of primary endpoints makes Lynparza the first PARP inhibitor to demonstrate clinical benefit as an adjuvant treatment in early breast cancer.
Other than Lynparza, Pfizer’s Talzenna is the only PARP inhibitor, which is approved for gBRCAm HER2-negative locally advanced or metastatic breast cancer. Unfortunately, Company has terminated the Phase II trial in the neoadjuvant setting due to a change in clinical development strategy (NCT03499353). Most companies cannot cement their position in PARP inhibitors, as either their candidates have failed or are in the early stage of development: Abbvie’s veliparib has failed as a neoadjuvant treatment option in triple-negative early-stage breast cancer, and Clovis Oncology’s Rubraca and GSK’s Zejula, which are being evaluated in academic-sponsored neoadjuvant trials, are in the early phase. None of them has been successful in the advanced or adjuvant setting.
The early breast cancer truimph could give Astrazeneca/Merck edge over its PARP inhibitors rival Pfizer’s Talzenna, which is approved for advanced setting. Considering the encouraging results for the primary endpoint, AstraZeneca and Merck are planning to file for approval of Lynparza as a treatment option in the adjuvant setting for gBRCAm, HER2-negative early-stage breast cancer in the second half of 2021 in the US, EU, and Japan; and in 2022 in China. The initial signs for Lynparza are good, and with no competitor in sight, positive results might further fuel its dominance as a PARP inhibitor in breast cancer.
Astrazeneca has a strong head start in the early/adjuvant setting, but the robust data is still pending. We are quite optimistic for Lynparza, as it might be the standard of care in the adjuvant setting as well, if approved. On becoming the standard of care in the adjuvant setting for gBRCAm HER2-negative early-stage breast cancer, the key healthcare agencies around the world might recommend genetic testing essential to look for these biomarkers in the adjuvant setting.