ASCO 2021: The science behind olaparib’s promise shown in the OlympiA early breast cancer trial

Image: Olaparib pill bottle marked clinical trials (Credit: Jan Chlebik for the ICR, 2014) 

Today, the results from a major clinical trial were revealed at ASCO. The findings represent an important step in our research’s journey from discovery to drug development to transformative patient care.

The results, presented at the ASCO 2021 conference and published in the New England Journal of Medicine, show that giving the targeted cancer drug olaparib after chemotherapy cuts the risk of breast cancer returning or spreading in women who have inherited mutations in their BRCA1 or BRCA2 genes.

The findings establish olaparib – already used to treat advanced ovarian, breast, prostate and pancreatic cancer – as the first drug that targets the specific biology of the BRCA genes to show success for treating early-stage breast cancer with an inherited BRCA1 or BRCA2 mutation.

The OlympiA Phase III trial was coordinated internationally across multiple partners by the Breast International Group which constitutes a network of over 50 academic breast cancer research groups.

This worldwide effort took years and the science underpinning it goes back decades. The ICR, with funding support from many partners including Breast Cancer Now and Cancer Research UK, worked to discover how to use olaparib and other PARP inhibitor drugs for patients with mutations in their BRCA1 or BRCA2 genes, or faults in other DNA repair genes.

Professor Andrew Tutt, Director of the Breast Cancer Now Toby Robins Research Centre at the ICR and the Breast Cancer Now Research Unit at King’s College London, Chair of the OlympiA steering committee explains:

“The ICR has been involved in the development of PARP inhibitors for many years. And it's been a privilege to be part of a team of a big team who have been on that journey here.

“The story is really one that begins with understanding the BRCA1 and BRCA2 genes... But rather than just identifying the risk, what ICR scientists did was think how we can use that information to design a targeted treatment approach. ICR researchers found evidence that we could target an Achilles heel specific to the cancer cells with PARP inhibitors and then have been partnering in a global effort with doctors, trials groups and patients ever since. That partnership continues with OlympiA.”

The discovery of the BRCA2 gene

Back in the early 1990s, researchers around the world were engaged in a race to identify genes helping to determine breast cancer risk. Researchers in the US first identified the BRCA1 gene – but while this explained many inherited cases of breast cancer, scientists were sure that there was another important gene out there.

In 1995, a research team led by Professor Mike Stratton and Professor Alan Ashworth at the ICR identified the second breast cancer susceptibility gene, BRCA2. After pinpointing the gene to chromosome 13 they found disease-causing mutations which were also seen in families with a history of breast cancer. The next step would be not only to identify the genetic risk but understand the biological mechanism behind it.

Synthetic lethality: Targeting cancer’s Achilles’ heel

Around this time Professor Tutt was taking on a traineeship at the ICR’s partner hospital The Royal Marsden NHS Foundation Trust. He had been working as a Clinical Oncologist but knew he wanted to understand cancer more deeply to develop better treatments and jumped at the chance to learn more about cancer from a biological perspective.

Under Professor Ashworth’s supervision, Andrew Tutt worked as a PhD student with a wider group in the Ashworth laboratory to uncover the functions of the BRCA2 gene. We now know that both the BRCA1 and BRCA2 genes have an important role in repairing DNA breaks that occur in cells, and that’s why a mutation in a BRCA gene can contribute to cancer development. 

Professor Tutt, Professor Chris Lord and Professor Alan Ashworth would go on to show that drugs called PARP inhibitors were particularly good at killing cancer cells with BRCA mutations – uncovering a concept called ‘synthetic lethality’ which can be used to develop treatments that selectively target weaknesses in cancer cells and leave healthy cells relatively unharmed.

PARP inhibitors: A new class of cancer drugs

With clear scientific results, the team set out to develop clinical trials to see if they could translate these findings. These early trials were led by Professor Johann de Bono, Professor Stan Kaye and Professor Andrew Tutt.

PARP inhibitors represented an entirely new class of drugs to treat cancer in a targeted way. One of the key successes was olaparib and has gone on to help patients with particular forms of cancer associated with inherited BRCA mutations, including ovarian cancer.

In 2014, the European Medicines Agency approved olaparib for women with ovarian cancer who have an inherited BRCA1 or BRCA2 mutation. This marked the first cancer drug to be approved that is directed against an inherited genetic mutation.

In 2017, our researchers showed how olaparib benefitted women with advanced breast cancer. The European Medicines Agency has approved the use of olaparib for women advanced breast cancer and an inherited BRCA mutation.

The next chapter

This journey has been a deeply rewarding scientific and personal journey for Professor Tutt. He recalls how emotional it was to first see the results of the OlympiA trial:

“Having had the privilege of being been involved in this work from the beginning, it was a moment of great elation for me when we completed the trial and knew we would have answered an really important question about targeted treatment for women who had inherited these faults in the BRCA1 or BRCA2 genes”

“And then to see a result -- which for the first time suggested that this targeted approach we had developed in our laboratories might reduce life threatening recurrence of breast cancer for these women – well surely that is why any of us would get up in the morning.”

The OlympiA trial results represent a new chapter in this story as our researchers work to better identify the patients who can benefit the most from these drugs, to target resistance if it develops and to discover additional smarter and kinder treatments.

Olaparib is mainly used for more advanced forms of cancer but this trial raises the possibility that olaparib could be effective early in disease in other forms of genetic BRCA1/2 associated cancers. Further trials will have to be developed to explore this possibility and there is still much more work to be done.

Professor Tutt said: “This has taken some years to achieve, but it's been quicker than in many other situations because of our ability to link up all the important expertise within the ICR with that of our many collaborative partners in academia and industry outside the ICR.”