Olaparib: realising the promise of synthetic lethality

Highlights from Pioneering Research: the Cancer Research UK annual research publication 2014/15.

In December 2014, the drug olaparib (Lynparza) became the first of a new class of treatments known as PARP inhibitors to be licensed for clinical use, heralding in a new era for personalised, targeted treatment — and turning the promise of ‘synthetic lethality’ into reality.

The journey of taking olaparib to market took almost two decades of hard work underpinned by the ingenuity and combined efforts of many individuals. Along the way there was a collective ‘eureka’ moment for two of our researchers, Professors Alan Ashworth and Steve Jackson, who spotted a synergy between their basic research that is now reaping rewards in the clinic.

In the mid-1990s, Ashworth, then at the Institute of Cancer Research in London, was a key member of the group that discovered the DNA repair gene BRCA2, and identified mutations in this gene in families with high incidence of breast cancer. His lab subsequently defined a role for BRCA2 in repairing DNA double-strand breaks. This work led Ashworth to hypothesise that DNA-repair defects associated with BRCA mutations might be targeted by drugs. Around the same time in Cambridge, Jackson was developing drugs to block DNA repair processes in cancer cells. One target in his sights was an enzyme called poly (ADP-ribose) polymerase (PARP) which is required to mend single-strand DNA breaks.

Fresh perspective

Ashworth and Jackson soon realised that they were trying to solve the same problem but from different perspectives. “The connection between PARP and BRCA transpired following a discussion where we considered the possibility that PARP inhibition might induce a specific form of DNA damage that BRCA mutant cells would find very difficult to repair,” Ashworth explains.

Together, they predicted that PARP inhibitors under investigation by Jackson might preferentially kill cancer cells harbouring BRCA mutations while sparing normal cells. These drugs were proposed to exploit synthetic lethality, whereby blocking one DNA repair pathway (e.g. with a PARP inhibitor) compromises cell survival only when the back-up pathway (e.g. BRCA) is disabled.

We started helping Mike Stratton identify the BRCA2 gene in 1995. Little did we know that this would eventually lead us to inventing a new treatment for BRCA mutation carriers and having it approved almost 20 years later. Funding from Cancer Research UK throughout this period was critical in making this happen.

— Professor Alan Ashworth (University of California, San Francisco)

In December 1997, Jackson founded the spin-out company KuDOS with Cancer Research Technology and the University of Cambridge to commercialise his academic work on DNA repair. “The involvement of CRUK was crucial,” says Jackson, “because it provided seed funding to establish platforms for screening and preclinical studies”. KuDOS developed several specific and potent inhibitors of DNA repair proteins and worked closely with Ashworth’s team in London to test their efficacy in cell lines with BRCA mutations. As predicted, the leading KuDOS PARP inhibitor — olaparib — was strikingly effective in this model of inherited cancer.

However, it quickly became apparent that the financial clout of a large, established pharmaceutical company was required to fully realise the potential of olaparib. The favourable laboratory results obtained using KuDOS compounds did not go unnoticed by industry. In 2005, seeking an opportunity to boost its oncology development pipeline, AstraZeneca brokered a £120 million deal to acquire KuDOS and all of its assets. AstraZeneca then took olaparib forward into clinical trials.

Realising clinical potential

The first Phase I study with olaparib was designed to test the synthetic lethality hypothesis in patients with BRCA mutations. It worked, and today is widely cited as a prime example of truly personalised medicine. Further studies followed, including a Phase II trial led by Jonathan Ledermann at the CRUK and UCL Cancer Trials Centre, providing vital evidence to support AstraZeneca’s regulatory submission. It showed impressive increases in progression-free survival and extension of ‘time to next treatment’ for patients with relapsed ovarian cancer, with a subgroup of ‘super responders’– heavily enriched for BRCA mutation carriers — still exhibiting disease control 2–3 years later. According to Ledermann, these outcomes were previously unheard of for chemotherapy in ovarian cancer.

Extending therapeutic reach

With the groundwork done, the hope now is that olaparib will be active against many different cancers either as a single agent or in combination with other therapies, regardless of BRCA status. Over 10% of human cancers exhibit ‘BRCAness’, a term coined by Ashworth’s team to describe tumours that have BRCA-like DNA repair defects but lack gene mutations. Preclinical data from KuDOS shows that PARP inhibitors increase sensitivity to radiotherapy and chemotherapy and might also be used to treat cancers with compromised DNA repair resulting from hypoxia.

“PARP inhibitors could represent the biggest development since the introduction of platinum-based chemotherapy drugs. For the first time, a drug is available that works in a defined subgroup of ovarian cancer patients with a specific predictive genetic marker. The current UK threshold for BRCA screening should, therefore, be reset to ensure that we do not miss the pool of people who are unaware that they have BRCA mutations.”

— Professor Jonathan Ledermann (Cancer Research UK and UCL Cancer Trials Centre)

Olaparib’s success has motivated companies to develop additional PARP inhibitors which are now being accelerated into the clinic. One such example rucaparib, developed by Clovis Oncology, received breakthrough therapy designation from the FDA in April as a treatment for women with BRCA-mutated advanced ovarian cancer, based on the results of the ARIEL2 study. The company plans to seek regulatory approval for the drug in 2016. A number of CRUK studies are testing PARP inhibitors for broader indications (see Table) and olaparib is tipped to pave the way for other synthetic lethality approaches over the coming years allowing even more patients to benefit.

Cancer Research UK continues to support links between academia and industry to ensure that basic research in this area brings future gains for patients. Jackson remarks: “It is my belief that strong partnerships between academic groups, clinicians, biotech and pharma will continue to play crucial roles in producing the next generations of cancer therapies.”

At the time of going to print in June 2015, NICE had made an interim decision not to recommend olaparib for ovarian cancer patients with BRCA gene mutations. CRUK’s Chief Clinician, Professor Peter Johnson, said of this decision: “NICE’s provisional decision not to recommend olaparib for the small number of women with ovarian cancer and mutations in the BRCA gene is hard to understand. This is a great example of personalised medicine which offers a new treatment for a type of cancer where we have made little progress in the last decade and where there is a clear need for different approaches. The NHS can’t afford to ignore important innovations like this while our ovarian cancer survival rates lag behind the rest of the developed world. We hope that the manufacturer and NICE can work together quickly to reach an agreement which allows the drug to be made available when NICE issues its final guidance.”

This story was originally published in Pioneering Research: Cancer Research UK’s annual research publication for 2014/15. Find more at cruk.org/pioneeringresearch

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