Adjuvant olaparib extends disease-free survival in BRCA carriers

After 1 year of adjuvant therapy with the PARP inhibitor Olaparib, patients with high-risk, early-stage, HER2-negative breast cancer with BRCA1/2 germline mutations demonstrated extended disease-free survival. Medicom’s journalist interviewed Dr. Judy Ellen Garber, the director of the Center for Cancer Genetics and Prevention at the Dana-Farber Cancer Institute, a breast cancer oncologist, and a professor of medicine at Harvard Medical School.

In June 2021, a prespecified interim analysis of the phase 3 OlympiA trial (NCT02032823) was presented at the 2021 American Society of Clinical Oncology (Abstract LBA1), and were also published in the June 24^th edition of the New England Journal of Medicine [1,2]. At 24 months of follow-up, 85.9% of patients treated with adjuvant olaparib were alive and free of recurrent invasive cancer and new second cancer (ie, invasive disease–free survival) compared with 77.1% of placebo-treated patients. The estimated 3-year distant disease–free survival rate was 87.5% for olaparib vs 80.4% with placebo..

Medicom spoke with Dr. Garber about the implications of OlympiA.

Thank you for joining us Dr. Garber. Was accruing large number of women with germline BRCA mutations difficult?

‘’Well, I certainly would say that one of the most important things to me about the OlympiA trial was that it really showed that women with germline mutations would participate in research, and would do that around the world. There was a lot of skepticism about whether a trial like this could accrue sufficient numbers, especially given cultural differences in something as personal as a germline mutation.

Yet- it was done, and it was done really well. It was a very dedicated, large group of people from around the world who participated: the patients of course, and their providers as well. And I think we should not underestimate the impact of something like that for women with mutations going forward.”

With the result of OlympiA, how will that change the treatment of early breast cancer or newly diagnosed breast cancer in and how will we make sure that the right people benefit?

“Certainly, we have not been testing all breast cancer patients at diagnosis looking to see if they had a BRCA mutation, although we have been testing a lot. Most of the guidelines allow for testing women with triple-negative breast cancer, which has a higher risk of having at least a BRCA1 mutation, and younger women and women with very small amounts of family history.

That was partly because women would use the information to make surgical decisions. Would they have a bilateral mastectomy instead of a lumpectomy and radiation? Now you have another reason that women with higher risk disease might want to change their treatment. So the OlympiA trial was not for all early breast cancer, it was only for early breast cancer where there was a high risk that it could come back after treatment, Those women had either triple-negative breast cancer, or had had neoadjuvant treatment chemotherapy first before surgery and still had tumor left at the time of surgery, or they had estrogen receptor-positive breast cancer, and a lot of disease. They had to have at least four positive lymph nodes or a lot of disease left after treatment. All patients enrlled had a lot of disease.

Women who already know they have a BRCA mutation undergo regular screening by mammograms and MRIs, and hopefully they won't be diagnosed when they have a lot of breast cancer that would be eligible for the trial.

I do think that the results of OlympiA trial will make more people think about breast cancer genetic testing. I hope that they'll remember estrogen receptor positive disease as well as triple-negative disease, not HER2-positive disease though. This information helps guide treatment decisions.

The United States is actually pretty good about paying for genetic testing, especially in breast cancer patients. Most of them do not get into the nitty-gritty details of exactly how people make criteria and they covered the test which is relatively inexpensive, certainly compared to cancer treatment. I do think that there has been, in my opinion, remarkably consistent coverage for targeted therapies.

Targeted therapies tend to be very specific. They tend to be very expensive. That is going to be the case here too. I think private insurers will cover everything, but the federal government and state insurers, like Medicaid, Medicare, will be stricter, but I think they are going to have to cover genetic testing too. Should the government negotiate better on price? Maybe, but I do not think that people who meet the criteria will have as much trouble getting coverage as you might expect.”

The results from the OlympiA trial were not conclusive with regard to overall survival at this point with the short follow-up, but given the trends that we have seen and taking the treatment into an earlier stage of breast cancer, do you think that we can be cautiously hopeful with regard to those outcomes?

“I think we can be cautiously optimistic that the trial, which has shown such important effects on recurrence or disease-free survival, that there will be overall survival advantage, but, you know, I think we have to be thorough and careful. These drugs are not without side effects. Patients did really well on the study, but they were followed for a short time. We have to be as rigorous about PARP nhibitors as others. And yet -absolutely- we all hope that there will be an improvement.”

What would be the next steps in investigating the optimal treatment for this patient group?

“Finding the best regimen. We can look at Herceptin as a guide or trastuzumab in patients whose, who really were very similar. When they first started treating HER2-positive patients with targeted therapy, just like this study, they had a great delay in recurrence and then they showed improvement with a year.

And then they did a study comparing 2 years to 1 year, and 2 years was not better. And then they did studies looking at 6 months and most of them are also not as good as 1 year adjuvant therapy. So somehow we lucked out with a year. Why a year?  I think if shorter could be as good, that would be great. Although I suspect that the first studies will be to ask, are there groups who do not have as much disease as people in OlympiA who still benefit from a PARP inhibitor?

There are probably subgroups of patients who could get a PARP inhibitor instead of chemotherapy or get less chemotherapy and some PARP inhibitor and do as well. That will probably going to be the focus of the next studies before we get to debate how short a time can we get away with.”

Will olaparib prevent ovarian cancer in these patients? Is there any prophylactic advantage do you think?

“I would be hopeful that PARP inhibitors, which have been so effective in the treatment of ovarian cancer could prevent second cancers in BRCA carriers, could prevent ovarian cancer, could reduce the risk at least of even pancreas or prostate cancer in men. But the truth is that many women will not wait to find out that once they have had their breast cancer and been through all of the treatment and everything else that they will surgically reduce their risk by removing their ovaries or at least the fallopian tubes. And I do think that one of the other benefits of the OlympiA trial is that it opens the door for thinking about PARP inhibitors for prevention. Here are women who had cancer, but are expected to survive and so are relatively healthy and stayed relatively healthy with treatment. This allowed people to think maybe this could actually be a risk-reducing agent for breast, for ovarian, for all these things.

Although I have to say, application in a prophylactic setting would only be after very careful, thorough evaluation and thinking about prevention in a different way. We are not going to be putting people on years of PARP inhibitor to try and reduce their cancer risk… that would probably cause more trouble. But at least we can think creatively about whether small doses or small intermittent exposures could prevent cancer or at least delay it.

Imagine if we did not have to be doing surgeries on such young women.”

 

1. Tutt A, Garber JE et al, J Clin Oncol 39, 2021 (suppl 15; abstr LBA1).
2. Tutt ANJ, Garber JE, et al. Adjuvant Olaparib for Patients with BRCA1- or BRCA2-Mutated Breast Cancer. N Engl J Med. 2021 Jun 24;384(25):2394-2405.

 

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Posted on 6 August, 202115 February, 2024