Olaparib Protects Patients From High-Risk Cancer Recurrences

SAN ANTONIO — Nearly 10 years along patients with high-risk BRCA-positive breast cancers who had been treated with the poly(ADP-ribose) polymerase (PARP) inhibitor olaparib (Lynparza) following standard therapy in the phase 3 OlympiA trial continue to have better survival outcomes than patients who had received placebo, investigators reported.

At a median follow-up of 6.1 years, with the longest follow-up out to 9.6 years, the 6-year rate of invasive disease-free survival (IDFS) was 79.6% for patients initially randomized to receive olaparib compared with 70.3% for those who had been assigned to receive placebo. 

The data, from a prespecified analysis conducted 10 years after the first patient was randomized in the trial, translated into a 35% overall reduction in risk for invasive disease with olapraib, reported Judy E. Garber, MD, MPH, from the Dana-Farber Cancer Institute in Boston.

“These data continue to support the use of adjuvant olaparib as standard of care for patients with germline BRCA pathogenic variants and high-risk BRCA-negative breast cancer, and the data emphasize the importance of considering germline testing for treatment planning,” she said in an oral abstract presentation (Abstract GS1-09) at the San Antonio Breast Cancer Symposium 2024. 

OlympiA Details

In the OlympiA trial, which was launched in 2014, patients with germline pathogenic or likely pathogenic mutations in BRCA1 and/or BRCA2 and who were HER2-negative were eligible. Because pathogenic mutations in BRCA1 are primarily found in triple-negative breast cancer (TNBC), and mutations in BRCA2 are primarily found in estrogen receptor-positive (ER+) breast cancer, patients with both cancer types were enrolled. In both the olaparib and placebo arms of the trial, about 82% of patients had TNBC.

Eligible patients had stage II or III cancers, or did not have a pathologic complete response after neoadjuvant chemotherapy.

Patients first underwent either neoadjuvant or adjuvant chemotherapy, with or without radiotherapy, and after stratification for tumor type, neoadjuvant vs adjuvant therapy, and whether they had previously received platinum-based chemotherapy, the patients were randomized to receive either olaparib 300 mg twice daily for 1 year, or placebo.

The trial met its primary endpoint of IDFS at the first interim analysis in March of 2020, and the secondary endpoint of improved overall survival (OS) at the second interim analysis in July of 2021. 

Ten-Year Results

As noted before, the 6-year IDFS was significantly higher in the olaparib group, with an absolute difference over placebo of 9.4%. The stratified hazard ratio (HR) for invasive disease with olaparib was 0.65 (This and all following comparison had a statistically significant confidence interval.) The beneficial effect of the PARP inhibitor was seen across all subgroups, including whether prior chemotherapy was in the neoadjuvant or adjuvant setting, prior platinum exposure, hormone receptor status, or whether patients had mutations in either BRCA1 or BRCA2, or both.

A similar 6-year benefit was seen in distant disease-free survival, with 83.5% of patients in the olaparib arm vs 75.7% in the placebo arm having no distant metastases (stratified HR, 0.65), and in OS, with respective 6-year rates of 87.5% vs 83.2% (HR, 0.72).

Adverse events caused the death of five patients in the olaparib group and 10 in the placebo group. Adverse events of special interest at any time were under 10% in both study arms, but were numerically lower in the olaparib group. Garber noted that the rates of myelodysplastic syndrome or acute myeloid leukemia were low in both groups, with only four patients in the olaparib group (0.4%) and six in the placebo group (0.7%) developing one of the hematologic malignancies.

New primary cancers occurred in a total of 4.9% of patients on olaparib and 7.5% on placebo. New breast cancers occurred in 2.9% and 4.0% of patients, respectively.

Benefits Maintained

“These are good results for our patients,” commented Kate Lathrop, MD, UT Health San Antonio, who moderated a media briefing where Garber discussed the study prior to her presentation in a general session.

Lathrop noted that the finding of benefits among the smaller subset of patients with hormone receptor-positive disease “is very encouraging,” but added, however, that although patients generally tolerate PARP inhibitors fairly well, there are still toxicities that might give clinicians pause when considering whether to prescribe these drugs. She gave as an example cytopenias that can occur when the PARP inhibitors are given in the adjuvant setting, when patients may already be myelosuppressed from chemotherapy. The evidence of a clear, sustained benefit for high-risk patients with the use of a PARP inhibitor may make the decision easier, she suggested.

In the question and answer session following Garber’s presentation, Daniel F. Hayes, MD, from the University of Michigan, Ann Arbor, Mich., asked whether chemoprevention trials using olaparib were being considered.

“Yes, in fact, although I don’t think anyone would want to give continuous olaparib dosing for chemoprevention, there is a question of whether one could give intermittent dosing: maybe you can remove those cells that had begun to transform if this were done periodically for short exposures,” she said.

She noted that her group at Dana-Farber is currently exploring this idea.

The OlympiA trial was sponsored by AstraZeneca. Garber disclosed research support from Ambry Genetics and Invitae Genetics, and serving as co-principal investigator on trials supported by NRG Oncology and Amgen. Lathrop did not report a conflict of interest. Hayes has disclosed institutional research funding from AstraZeneca and others, and a consulting/advisory role for various companies, not including AstraZeneca. 

Neil Osterweil, an award-winning medical journalist, is a long-standing and frequent contributor to Medscape Medical News.