Our research impact: PARP inhibitors

The PARP inhibitor story begins in the mid-1990s when a team of ICR scientists – including our former Chief Executive Professor Alan Ashworth and Sir Mike Stratton, now Director of the Wellcome Trust Sanger Institute – first discovered the breast cancer susceptibility gene, BRCA2. Professor Ashworth’s team went on to find that the BRCA2 protein helps to repair a specific type of DNA damage called double-strand breaks. When BRCA2 is faulty, cells introduce mistakes into their DNA than can lead to cancer.

Professor Chris Lord, Professor of Cancer Genomics in the Breast Cancer Now Toby Robins Research Centre at The Institute of Cancer Research (ICR), describes what happened next.

“The immediate clinical impact of the identification of BRCA1 and BRCA2 was that women with inherited faults in those genes could choose to have prophylactic surgery to limit their chance of developing breast or ovarian cancer. But when I joined the lab as a postdoc, one of the questions that Alan set the whole laboratory was to think about how we could help improve treatment for patients with BRCA-deficient cancers.”

A vital breakthrough came from a conversation between Professor Ashworth and Professor Steve Jackson, who had set up a company called KuDOS (later acquired by AstraZeneca) to develop drugs that block DNA repair proteins. They both realised that blocking another DNA repair pathway in BRCA-defective cells that are already struggling to fix faults in their genetic material had the potential to tip them over the edge, making them unviable.

Image: Professor Chris Lord, Professor of Cancer Genomics in the Breast Cancer Now Toby Robins Research Centre at the ICR

Synthetic lethality

The proposed new strategy was an example of the concept of ‘synthetic lethality’ – when a defect in one gene has a limited impact on a cell but causes cell death when combined with blocking the function of another gene product.

Professor Ashworth’s ICR team quickly set about testing some of KuDOS’s inhibitors on cancer cells with faulty BRCA genes. In 2005, they showed that compounds that block the activity of a DNA repair protein called PARP could selectively kill cancer cells with a faulty BRCA1 or BRCA2 gene, leaving normal cells relatively unharmed. In parallel, researchers in Sheffield and Newcastle who were working on the same concept also demonstrated that PARP inhibitors could be used as a tailored treatment for patients with BRCA2 mutations.

“The scale of the effect was enormous,” reflects Lord. “A lot of scientists would say that a lot of the great discoveries they make are partially serendipitous – but you need to be mentally alert to notice those things. Luckily, Nuala McCabe and Hannah Farmer, the two postdocs in the lab who first noticed the effects of PARP inhibitors in BRCA1 or BRCA2 mutant cells, were very alert to what they had found.”

Further preclinical tests at the ICR using PARP inhibitors in mice with BRCA-defective tumours gave similar encouraging results. At the same time, the joint ICR-KuDOS team was able to make the first steps toward understanding how PARP inhibitors caused these effects. KuDOS went on to develop a drug (KU-0059436, later renamed AZD-2281 and then olaparib) that could be taken in tablet form.

Because these compounds killed cancer cells much more than healthy cells, the hope was that they would cause fewer side effects than traditional chemotherapies – a hypothesis that was rapidly tested in the clinic.

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From bench to bedside

The ICR team continued to contribute to the development of PARP inhibitors, working with the ICR and Royal Marsden’s Drug Development Unit on trials of olaparib. The world’s first phase I trial of olaparib was led by an ICR Clinician Scientist, Professor Johann de Bono, now Regius Professor of Experimental Medicine at the ICR and Director of Drug Development at the ICR and The Royal Marsden who designed the first clinical trial of a PARP inhibitor in BRCA-mutated cancers.

“I vividly remember going and sitting in the phase I clinical trials unit and discussing the design of the dose-finding single-agent study protocol with Johann where we included an expansion cohort enriched for BRCA mutation carriers,” reflects Professor Andrew Tutt, Professor of Breast Oncology in the Breast Cancer Now Toby Robins Research Centre at the ICR. “We also included biomarker testing to look for tell-tale DNA changes in patient blood and hair samples to confirm that the drug was hitting its target and working through the proposed mechanism as the dose increased.”

The results of the phase I trial, published in 2009, confirmed the original laboratory discoveries by demonstrating the exciting potential of olaparib for treating patients with advanced cancers who had faulty BRCA genes, including subsets of patients with breast, ovarian and prostate cancers. “We still have an ovarian cancer patient who took part in that first-in-human trial who has now been on the drug for more than 15-years and remains in complete remission from her cancer,” says de Bono.

Image: Professor Andrew Tutt, Professor of Breast Oncology in the Breast Cancer Now Toby Robins Research Centre at the ICR

Larger trials

Professor Tutt then led two phase II trials in advanced breast and ovarian cancer patients with faulty BRCA genes. The results of these studies, published in 2010, found olaparib shrank or stabilised tumours in up to a half of patients whose cancers were resistant to chemotherapy and established the most suitable dose – two 400mg tablets taken twice daily – to explore in further studies.

In 2012, another ICR Clinician Scientist, Professor Stan Kaye, led an international multi-centre phase II study of olaparib in patients with BRCA-deficient ovarian cancer.

These promising results led to additional phase II and phase III clinical trials in patients with inherited BRCA mutations. Based on the results from one of these studies, olaparib, which is also known by the brand name Lynparza, became the first cancer drug directed against an inherited genetic fault when it was licensed by the European Medicines Agency (EMA) and the US Food and Drug Administration (FDA) as a treatment for women with BRCA1 or BRCA2-mutated ovarian cancer in 2014.

The successful treatment of BRCA-mutant cancers with a PARP inhibitor was the first demonstration of the use of a synthetic lethal strategy in the clinic.

“This stimulated a huge amount of activity to look for other interactions that were associated with other cancer drivers,” says Lord. “Initially, there was a lot of academic activity but now there’s a lot on the commercial side too – the number of biotech companies based on exploiting the synthetic lethality principle is growing every day.”

Treating advanced prostate cancers

But the close collaboration between ICR laboratory scientists and clinicians did not stop at the point when olaparib entered clinical trials.

“When people think about the translational process, it’s often depicted as something getting handed over to the clinic and that’s it,” describes Lord. “But actually, it’s a bi-directional process – we didn’t put down our pipettes, but carried on working on PARP inhibitors in the laboratory.”

In 2006, Professor Ashworth’s ICR team showed that cancer cells with a deficiency in one of several other proteins involved in repairing DNA double-strand breaks by the same process as BRCA1 and BRCA2 – called homologous recombination repair (HRR) – are also susceptible to PARP inhibition.

“This was important as it suggested that PARP inhibitors could also be effective in cancers with other HRR defects, expanding the number of cancer patients who might benefit from the impact of these drugs,” explains Lord.

Based on the promising therapeutic exploitation of the synthetic lethality between PARP inhibition and BRCA mutation, Professor de Bono’s team predicted that olaparib could benefit a subset of prostate cancer patients whose tumours were resistant to existing treatments.

Together with Professor Emma Hall, Professor de Bono led a phase II clinical trial involving 50 men with treatment-resistant, advanced prostate cancer. The study, called TOPARP-A, found that up to 30% of men had tumours with DNA repair defects including mutations in BRCA2, BRCA1, PALB2, ATM, or HDAC2, detected by genomic testing – and these patients’ cancers responded particularly well to olaparib.

The study was also the first to show that ~12 per cent of all men with advanced prostate cancer had inherited DNA repair defects. This was later confirmed in further studies co-led by Professor de Bono, which led to changes to international guidelines recommending that all men with advanced prostate cancer should be tested for inherited mutations in DNA repair genes including BRCA2.

The TOPARP-A trial led seamlessly to TOPARP-B, which was the first study to direct the drug specifically to men whose prostate cancers had DNA repair defects that may sensitize to PARP inhibitors.

“We found impressive tumour shrinkage not only in men who had inherited BRCA mutations, but also responses in some patients with advanced disease who did not have faults in these genes,” says de Bono. “But virtually all the cancers that responded to the drug had an identifiable DNA repair defect.”

A major phase III clinical trial called PROfound, which was funded by AstraZeneca and led by Professor de Bono, showed that olaparib is more effective than targeted hormone therapy at keeping cancer in check in men with advanced prostate cancer whose tumours have faults in BRCA1, BRCA2 or other pre-selected HRR genes. The results from the study led to the landmark approval of olaparib in prostate cancer in the US and Europe in 2020.

“Olaparib became the first molecularly-stratified treatment for advanced prostate cancer,” says de Bono. “It made our team’s hard work feel worthwhile.”

Professor de Bono’s team, working as part of the SU2C Prostate Cancer Foundation Dream Team, also carried out a comprehensive mutation mapping study of prostate tumours that had spread elsewhere in the body – finding that ~20-30 per cent of patients with advanced prostate cancer could benefit from PARP inhibitor therapy.

Image: Professor Johann de Bono, Regius Professor of Experimental Medicine at the ICR and Director of Drug Development at the ICR and The Royal Marsden

Broader impact

Before the prostate cancer approvals, olaparib had already been used to treat tens of thousands of patients worldwide – and this number will only continue to rise. But the impact of PARP inhibitors extends beyond ovarian and prostate cancer – there has also been an impact on breast and pancreatic cancer. As of 2020, olaparib is approved in 76 countries for the treatment of advanced breast cancer, and in 55 countries including the US for advanced pancreatic cancer.

In March 2022, the latest results of the phase III OlympiA trial led by Professor Tutt showed that olaparib improves survival in women with early-stage breast cancer with an inherited BRCA1 or BRCA2 mutation. It found that adding the drug to standard treatment cuts the risk of women dying by 32 per cent – resulting in more women remaining cancer-free and becoming breast cancer survivors.

“OlympiA has shown that after selecting women with inherited BRCA mutations through genetic testing, we can use olaparib to directly target the weakness in their cancer and improve their survival,” says Professor Tutt, who chaired the OlympiA steering committee. “I hope to see BRCA1 and BRCA2 testing used for more women diagnosed with early-stage breast cancer, so that we can determine who can benefit from this personalised treatment approach.”

In 2020, AstraZeneca reported olaparib (Lynparza) sales of more than $776,000,000 worldwide compared with $198,000,000 in the previous year. Several other companies have also built upon the ICR’s work, also developing different PARP inhibitors that have been approved for the treatment of cancer. As of 2021, three other PARP inhibitors have also been licensed for treating advanced ovarian, breast or pancreatic cancers.

Changing lives

From the start of the search for the BRCA2 gene, how it works and how faults in it cause certain cancers, right through to the discovery and development of targeted drugs with synthetic lethal effects on the DNA repair defects in these tumours, the ICR has been at the heart of the PARP inhibitor story.

In April 2022, a group of researchers from the ICR and The Royal Marsden, including Professor Lord and Professor Tutt, were awarded one of the world’s most prestigious cancer research awards, The AACR Team Science Award, for their work that has transformed treatment for many patients with breast cancer.

The team was recognised for a series of seminal discoveries, which included the discovery of new therapeutic approaches, such as PARP inhibitors, that have changed how patients with BRCA1 and BRCA2 mutant breast cancer are tested and treated.

Both Professor Lord and Professor Tutt have continued to study why different types of cancer cells respond to PARP inhibitors and whether other synthetic lethal effects could be exploited to treat cancer. They hope to have more opportunities to translate more discoveries into tangible benefits for patients in the future.

“As a biologist, much of what we do might impact people’s lives in decades to come – if we’re lucky, within our lifetime. And to see something that’s had an impact on patients and their families in such a very short period of time is just an incredible privilege,” says Lord. “And professionally, it gives you the desire to do it again – for better or for worse, we’re impatient and intellectually greedy people!”

Professor Tutt is similarly passionate about his involvement in this research.

“I pinch myself frequently,” he says. “It’s a lot of hard work, but this is something people would give their eyeteeth for – the opportunity to work as part of a larger team to translate amazing fundamental science into clinical impact. I cannot think of a better reward.”