In 2021, the results of the global OlympiA Phase III trial of adjuvant olaparib for patients with BRCA1- or BRCA2-mutated breast cancer were published in the New England Journal of Medicine and heralded across news outlets and medical Twitter feeds as a landmark practice-changing breakthrough.

Although the paper was an important milestone for the double-blind, placebo-controlled study, it wasn't the real watershed moment for the team of investigators led by Houston Methodist oncology researcher Dr. Charles Geyer, principal investigator for the U.S. arm of the study, and Dr. Andrew Tutt, OlympiA global chair.

That moment actually came four months earlier, when an independent data monitoring committee concluded the trial had crossed the superiority boundary for its primary endpoint of invasive disease-free survival and recommended the primary analysis begin about a year early. The recommendation was made because olaparib demonstrated a sustainable clinically relevant treatment effect compared to a placebo.

From the outset, the study challenge was identifying newly diagnosed patients with higher risk breast cancer only found to have a BRCA gene mutation as part of their workup. Patients who already know they have BRCA gene mutations are carefully screened on a regular basis, and therefore developing cancers are often caught early enough that they are not considered high-risk disease.

"You're targeting a population where standard therapy can cure the majority but there's still a sizable minority who relapse so you have to do a large study to show the intervention can substantially bump up the cure rates," Dr. Geyer says about the trial, which followed 1,836 patients and spanned 420 centers, 23 countries, eight years and multiple international clinical trial networks.

"That's why it took a number of years of global accrual to get it done," adds Dr. Geyer. "But that's also why the results are considered definitive enough that olaparib will presumably get regulatory approval for this indication, and we expect to see an almost immediate change in the way things are done. For this population, this will now be standard of care."

Positive results, manageable side effects

In patients with high-risk HER2-negative early breast cancer and germline BRCA1 or BRCA2 pathogenic or likely pathogenic variants, the study found oral administration of olaparib for one year was associated with significantly longer survival free of recurrent cancer than a placebo. All patients had completed standard local treatment and neoadjuvant or adjuvant chemotherapy.

The three-year invasive disease-free survival was 85.9% in the group receiving standard therapies followed by olaparib and 77.1% in the group receiving standard therapies followed by placebo. Three-year distant disease-free survival was 87.5% in the treatment group and 80.4% in the placebo group.

"The population of patients who had passed away or had a recurrence of cancer at the time of the analysis was reduced 42% with the addition of this drug," Dr. Geyer explains. "The effect size was larger than what we had expected. It really is a compelling number, made even more compelling by the limited and manageable toxicity of the treatment."

Olaparib had minimal effects on global patient-reported quality of life, with limited adverse events. Nausea and gastrointestinal issues were the most frequently reported side effects, but they tended to decrease over time. Fatigue was reported by 40% of patients on the medication and 27% of patients on placebo, signaling that there may be some holdover effect from standard chemotherapy and radiation. Some patients became anemic towards the end of the treatment period, but, overall, very few patients had to discontinue therapy due to an inability to tolerate the drug.

Participants will be followed for 10 years to assess continued efficacy against recurrence of breast cancer, overall survival, occurrence of new cancers or development of potential late effects.

Inclusivity multiplies impact

An estimated 2.3 million people were diagnosed with breast cancer worldwide in 2020, and BRCA mutations are found in about 5%. Around 55%-65% of women with a BRCA1 variant and 45% of women with a BRCA2 variant will develop breast cancer before the age of 70. Of these, about one third will not be cured through standard therapy and instead will experience a refractory, recurrent or metastatic form of the disease.

"The curing opportunity in breast cancer really is at the time of initial diagnosis," says Dr. Geyer. "We did this study because there's clearly an unmet need to identify these patients and provide more effective treatments so that their outcomes can be as good as other breast cancer patients."

As the study design began to take shape, however, the research team realized that their germline BRCA mutation target needed to expand in order to achieve maximum impact with the therapy.

"OlympiA was originally designed to be a triple-negative breast cancer study only, but half of the breast cancers that develop in patients with BRCA2 mutations are estrogen receptor positive," Dr. Geyer says. "Also, there are patients who don't inherit a mutated BRCA gene, but their tumors very much look and act as if they do. Since this was going to be such a big multiyear effort, we did not want entire populations that could benefit from this treatment to have to wait another eight to 10 years until we could conduct a similar study just for them."

Because men can have BRCA mutations and high-risk breast cancer as well, a small number of male patients who fit the criteria were included in the trial.

A much-needed silver lining

The reason inclusivity was important in this study has to do with the way the drug works. Olaparib is a poly (ADP-ribose) polymerase (PARP) inhibitor, which are the first targeted treatments to block DNA damage response (DDR) in cells or tumors which harbor a deficiency in homologous recombination repair (HRR).

In other words, it can work anywhere HRR is deficient and genomic instability is present. Whether it's a BRCA1 or BRCA2 pathogenic variant, germline or somatic mutation doesn't matter.

"It's important where you arrive, not how you got there," Dr. Geyer explains. "The thing they have in common is they don't have functioning BRCA genes that code the proteins that form the foundation for high fidelity repair of damaged DNA. This results in genomic instability which allows the tumor cells to grow and progress, but the environment can't get too unstable or else the cancer cells will die. It's kind of a house of cards. These types of tumors become very dependent — almost addicted — to a secondary DNA repair mechanism that uses PARP."

PARP binds to the DNA in order to repair it. And when you give olaparib to the patient, it traps PARP on the DNA and gums up the works, which can be catastrophic for the cancer cells. At the same time, normal cells with functional BRCA can still repair DNA damage so the lethal damage is limited to the HRR deficient cancer cells.

"The BRCA genes were only recognized as existing about 30 years ago, so it's a nice completion story of decades of work that went into understanding how BRCA mutations result in increased risk for early onset cancers and developing drugs to uniquely target these cancers," Dr. Geyer says.

"Now we're at this point where we can tell patients with these cancers, 'Yes, you are at increased risk for cancer, but for the same reason you got the cancer, there's this very specific therapy that can work,' " Dr. Geyer adds. "It's a silver lining the BRCA community really needed because they've certainly been given enough bad news about what their gene mutation means for them and their families."

Next steps

Currently, olaparib and other PARP inhibitors are being used clinically and evaluated in a range of PARP-dependent tumor types with defects in the DDR pathway.

Dr. Geyer expects multiple additional follow-up studies to emerge from the OlympiA trial over the next several years. Those could include testing whether expanding genome sequencing requirements identifies more BRCA carriers; determining if the use of PARP inhibitors as frontline therapy in these patients can elicit a pathologically complete response; and analyzing why some patients who received the drug didn't respond.

"For me, this really highlights the importance of participating in and supporting clinical trials," Dr. Geyer emphasizes. "This is going to save many lives, and we only got it done because of a global group of investigators willing to collaborate and put in long hours and hard work over several years. But, ultimately, what is 'leading medicine' about if not efforts like this?"