AstraZeneca's ADP-ribose polymerase (PARP) inhibitor Lynparza (ingredient: olaparib) received attention at the 2021 American Society of Clinical Oncology (ASCO) by unveiling the results of the phase 3 OlympiA trial in early breast cancer patients.

The clinical trial, unveiled during the plenary session of this year's ASCO, used olaparib as post-surgery adjuvant treatment in 1,836 high-risk early breast cancer patients with a germline BRCA mutation (gBRCAm) 1 and 2.

The primary endpoint was invasive disease-free survival (iDFS), and the secondary endpoint was distant disease-free survival (DDFS) and overall survival (OS).

According to the results announced on Saturday (local time), in patients with gBRCA mutation-positive and HER2-negative high-risk early breast cancer, olaparib administered as adjuvant therapy after surgery for one year reduced the risk of recurrence, metastasis, and death by 42 percent compared with placebo.

Also, the three-year invasive disease-free survival rate (iDFS) was 85.9 percent in the olaparib group compared to 77.1 percent in the placebo group, while the three-year DDFS was 87.5 and 80.4 percent in the olaparib and placebo groups, indicating that olaparib reduced the risk of distant metastasis and death by 43 percent compared to placebo.

Despite seeing fewer deaths in the olaparib adjuvant group, however, the study showed not much of a significant difference regarding the OS between the two groups at the time of the interim analysis.

To get a better insight into the study, Korea Biomedical Review met with Professor Judy E. Garber, Director of the Center for Cancer Genetics and Prevention at Dana-Farber Cancer Institute and one of the investigators for OlympiA, to see what the results of the trial mean for early breast cancer patients.

Question: OlympiA's target patient group was limited to a group with a high risk of recurrence. What is the exact classification criterion for high-risk groups?

Answer: The study was limited to people with increased risk of recurrence, and those included patients with triple-negative breast cancer (TNBC) with tumors T2 or larger, which means the patient's tumor is larger than 20 millimeters, and patients with estrogen-receptor-positive (ER+) with more than four positive nodes. Also, if patients received neoadjuvant chemotherapy, they had to have a persistent disease in the end.

We limited the study to such a group because we didn't know whether a year of PARP inhibitor would be helpful to such patients as there are toxicity concerns.

For example, there are concerns about possible cumulative bone marrow toxicity with chemotherapy.

So the researchers believed that the study should focus on high-risk groups first that received the treatment that could receive the potential benefit of treatment.

Question: According to the study design, the use of olaparib was limited to one year. Is there any special reason?

A: Well, it would have been nice to know what the benefits would look like in advance. However, we did not, and again researchers are always titrating the risk and benefit.

I think a year was chosen as a compromise in hopes that it would be long enough, but not too long.

It is important to remember the Herceptin trials were a year versus two years, and two years did not show an advantage over the one-year data.

Therefore, we felt that the one year was a good compromise. And, of course, one question we will have to answer in the future will be to see if the shorter duration study is sufficient or a longer duration study is needed.

But at least we can begin with having the one-year data.

Question: At 2.5 years of the follow-up period, improvement in iDFS, the primary endpoint, and DDFS, the secondary endpoint, showed significant improvement. What do these findings suggest?

A: Certainly, they suggest that additional treatment in the form of olaparib following standard chemotherapy, surgery, and possibly radiation treatment for these patients offers a substantial advantage.

However, naturally, as oncologists, we are most comfortable when we have an overall survival advantage. And we're hopeful that the advantages that we have now seen up to this point will lead to an OS with further follow-up.

Question: How do you expect the results of this study to change the practice of treating patients with BRCA-mutated breast cancer?

A: I think it means there is a possibility, particularly for our TNBC and ER+ patients, that the additional treatment can offer an advantage beyond the standard chemotherapy and systemic therapy if they have the mutation.

Now the question, of course, would be this study group was too restrictive. Will the U.S. Food and Drug Administration, European Medicines Agency, and Asian regulatory bodies decide to open the data more broadly as that should affect testing and change who is eligible for the trial?

It will be a challenge to incorporate these data with other evidence of improvement for our TNBC patients in the form of immunotherapy or other drugs that have shown promise.

However, at least for now, I think we have data that show that these patients can benefit from the addition of a PARP inhibitor, and time will tell to what extent this can be generalized.

Question: Does this study mean that BRCA screening should be adapted in all early breast cancer patients?

A: I think that for patients who would have been eligible for the OlympiA trial, it does suggest that we should be looking to see if they are mutation carriers for BRCA 1 or 2 at least and possibly PALB2 (partner and localizer of BRCA2) if we extend the trial results.

This is because those patients had a significant advantage, at least in the iDFS, with the addition of a PARP inhibitor.

So I would say for at least for patients who would have been eligible for the trial, we should consider testing at this time.

Question: What needs to be confirmed further in this study?

A: The two most important things that need to be confirmed are naturally the benefits in OS and toxicity.

Regarding toxicity, the short-term toxicity of the drug was quite similar to what we all see in other settings and quite manageable.

However, we all have concerns about potential long-term toxicity in every trial, including bone marrow toxicity, and that is something that we will be following with great interest.