Andrew Tutt, MB ChB, PhD, FMedSci, on OlympiA: High-Risk BRCA-Positive Breast Cancer

Hello. I'm here in San Antonio where the OlympiA investigators, led by Dr. Judy Garber, have presented the OlympiA trial's third pre-planned analysis, 10 years after the first patient enrolled and with a median follow-up now of just over six years. The OlympiA trial was a trial where women who had HER2-negative breast cancer with a germline mutation in BRCA1 or BRCA2 were given either placebo or the PARP inhibitor olaparib in the hope of improving survival outcomes for these patients after they had already received standard-of-care systemic therapy (neoadjuvant or adjuvant chemotherapy) and definitive local treatment. This trial targets homologous recombination deficiency in these tumors and is agnostic in its approach to whether the patient has hormone receptor-positive or triple-negative disease. Now, at this 10-year endpoint, we're reporting again on all the important endpoints: the primary endpoint— invasive disease-free survival—and secondary endpoints—distant disease-free survival and overall survival. These are not tests of significance because they were previously met and reported in the prior analysis. What does the trial show? It shows that with this longer median follow-up of just over six years, the results of the trial remain valid and stable. For the primary endpoint of invasive disease-free survival, the hazard ratio is 0.65, reflecting a 35% improvement in the rate of invasive disease-free survival events. The absolute difference is 9.4% at the six-year median follow-up point. For distant disease-free survival, there is again a 35% improvement in the treatment arm, with a hazard ratio of 0.65 and an absolute difference of 7.8%. Importantly, for overall survival, there is an absolute difference slightly higher than previously at 4.4%, representing a 28% improvement in the hazard of death overall. We were also able to present data broken out by hormone receptor-positive or triple-negative groups. These results show that the effect is consistent, whether the patient has triple-negative breast cancer or hormone receptor-positive breast cancer. Since the trial began slightly later for those with hormone receptor-positive disease, the number of women at longer follow-up points is smaller, making the results less stable at those points. Longer follow-up is planned, with a final report expected around 2029. We also examined long-term side effects. Importantly, there was no increase—and numerically fewer—adverse events of special interest in the olaparib group compared to placebo. This was a double-blind, placebo-controlled trial. Key adverse events examined included rates of acute myeloid leukemia or myelodysplastic syndrome, which showed no increase, and in fact, numerically lower rates in the olaparib treatment arm. Other new primary malignancies, which cancer treatments can sometimes increase, were also numerically fewer in the olaparib group compared to placebo, which is reassuring. We also looked at other cancers that occur more frequently in BRCA1 and BRCA2 germline mutation carriers. It was hypothesized that olaparib might reduce the risk of these cancers by targeting pre-malignant cells in the breast or ovary. Numerically, we observed reductions in breast and ovarian cancer incidences. This analysis is complex due to the influence of risk-reducing surgeries, such as mastectomies and oophorectomies. However, these surgeries were balanced between the two arms, and despite this, the overall rate of new invasive breast cancers, contralateral breast cancers, or new ovarian or fallopian tube malignancies was numerically lower in the olaparib group compared to placebo. In conclusion, this remains an important medicine for patients with germline mutations and HER2-negative breast cancer who have received chemotherapy, regardless of hormone receptor status. The long-term safety signals are favorable, with no evidence of significant long-term side effects, and olaparib improves survival. This underscores the importance of genetic testing for patients who may be eligible for this treatment to identify those with relevant mutations. Continued follow-up in this study will provide further insights into any late side effects or the impact on future secondary cancers.