Adjuvant olaparib prolongs survival for certain patients with early breast cancer
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Adjuvant olaparib significantly extended OS among patients with HER2-negative high-risk early-stage breast cancer and germline BRCA1/BRCA2 mutations, according to results of the randomized phase 3 OlympiA study.
The findings, presented during an ESMO Virtual Plenary session, also showed olaparib (Lynparza; AstraZeneca, Merck), a poly(ADP)ribose (PARP) inhibitor, improved invasive DFS and distant DFS and had an acceptable safety profile.
Rationale and methods
Women and men with germline BRCA mutations have a substantially higher risk for developing breast cancer at younger ages, Charles E. Geyer Jr., MD, FACP, medical oncologist and breast cancer specialist and chief scientific officer at NSABP, told Healio.
“Almost 91% of all [patients with breast cancer] in the U.S. are diagnosed at an early stage of disease, and BRCA mutations are found in approximately 5% to 10% of these patients,” he said. “Patients with germline BRCA mutations tend to have aggressive subtypes of breast cancer and while standard treatments that include chemotherapy, surgery and radiation therapy have improved outcomes, some of these patients remain at higher risk for disease recurrence and have had an unmet need for additional effective therapies to reduce this persistent elevated risk.”
Geyer said breast cancers that develop in patients with germline BRCA mutations lack a functioning critical DNA repair pathway, so the cancer cells must rely on an alternative backup pathway that utilizes the PARP protein to repair DNA replication errors as the cancer cells divide.
“If these errors cannot be corrected because of inhibition of PARP by drug treatment, the cancer cells will die,” he said. “This sensitivity to PARP inhibitors occurs in cells or tumors that harbor a deficiency in homologous recombination repair, such as those with mutations in BRCA1 and/or BRCA2.”
OlympiA sought to determine whether administration of the PARP inhibitor olaparib for 1 year after completion of standard therapies for high-risk, HER2-negative early breast cancer would reduce the risk for recurrence of breast cancer and death.
Researchers randomly assigned 1,836 patients 1:1 to 1 year of continuous oral olaparib dosed at 300 mg twice daily (n = 921; median age, 42 years) or placebo (n = 915; median age, 43 years).
Andrew Tutt, MB ChB, PhD, professor of oncology at Institute of Cancer Research in London and King’s College London, presented results of the second prespecified analysis of OS and updated invasive DFS, distant DFS and safety descriptive analyses, planned after 330 invasive DFS events. Median follow-up was 3.5 years.
Key findings
Results showed olaparib significantly improved OS compared with placebo (HR = 0.68; 98.5% CI, 0.47-0.97), with 4-year OS rates of 89.8% with olaparib vs. 86.4% with placebo (difference, 3.4%; 95% CI, 0.1 to 6.8).
Moreover, researchers observed improvements in invasive DFS with olaparib (HR = 0.63; 95% CI, 0.5-0.78), with 4-year rates of 82.7% vs. 75.4% (difference, 7.3%; 95% CI, 3-11.5), as well as improvements in distant DFS (HR = 0.61; 95% CI, 0.48-0.77), with 4-year rates of 86.5% vs. 79.1% (difference, 7.4%; 95% CI, 3.6-11.3).
All patient subgroups assigned olaparib experienced benefit, researchers noted.
About 10% of patients in the olaparib group discontinued treatment because of an adverse reaction. Grade 3 or greater adverse events that occurred among 1% or more of patients assigned olaparib included anemia (8.7%), neutropenia (4.9%), leukopenia (3%), fatigue (1.8%) and lymphocytopenia (1.3%).
Researchers observed no new serious adverse events with olaparib and no new cases of myelodysplastic syndrome/acute myeloid leukemia.
Implications
Geyer noted that primary results of the OlympiA trial, supported by the updated OS data, formed the basis for the recent FDA approval of olaparib for the adjuvant treatment of patients with germline BRCA-mutated, HER2-negative high-risk early breast cancer who received chemotherapy either before or after surgery.
“The approval of olaparib in this setting brings a new, personalized oral treatment option to people living with early breast cancer in the U.S. with a germline BRCA1 or BRCA2 mutation,” he said. “Early breast cancer represents a critical opportunity to treat with curative intent. Germline BRCA mutations are actionable biomarkers and testing for these mutations at diagnosis is an important step that can help inform treatment decisions, including identifying patients who may be eligible for olaparib in this setting.”
Additional follow-up of the OlympiA trial will continue out to 10 years in order to better understand the effectiveness of the therapy throughout time and check for any late toxicities, Geyer added.
“This will also provide important information on the potential of olaparib to reduce the risk for development of new second primary cancers, which remains an ongoing risk for patients with germline BRCA mutations, even if their initial breast cancer was successfully treated. We will also study breast cancers that still occur with olaparib to understand mechanisms of resistance that may help identify even more effective therapies than olaparib.”
References:
Lynparza (Olaparib) reduced risk of death by 32% in patients with germline BRCA-mutated, HER2-negative high-risk early breast cancer in phase 3 OlympiA trial. Available at: https://www.merck.com/news/lynparza-olaparib-reduced-risk-of-death-by-32-in-patients-with-germline-brca-mutated-her2-negative-high-risk-early-breast-cancer-in-phase-3-olympia-trial/. Published March 16, 2022. Accessed March 20, 2022.
Tutt A, et al. Abstract VP1-2022. Presented at: ESMO Virtual Plenary; March 16, 2022.
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Tutt A, et al. Abstract VP1-2022. Presented at: ESMO Virtual Plenary; March 16, 2022.
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