Several different PARP inhibitors currently in clinical development. PARP and inhibitor
*Edit 18/12/14* – This drug has now been approved by the European Commission for its use within the European Union.
*Edit 01/06/15* – NICE has provisionally turned down olaparib for use on the NHS in England – final decision expected in September 2015
*Edit 22/12/15 – NICE has approved the use of olapraib (Lynparza)for women with ovarian cancer who have BRCA1 or BRCA2 mutations in their tumours and have responded to three rounds of platinum-based chemotherapy.
Designed to target cancers in people carrying inherited faults in the BRCA1 or BRCA2 genes, PARP inhibitors have been tested in clinical trials for patients with breast, ovarian and prostate cancer caused by these genetic flaws. However, the journey from the lab to the clinic has been far from smooth, and the results have been promising but variable (including a strange case of scientific ‘mistaken identity’).
Now one of these drugs, olaparib (formerly known as AZD-2281or KU-0059436) from the pharmaceutical company AstraZeneca has received a positive recommendation from the Committee for Medicinal Products for Human Use (CHMP), part of the European Medicines Agency (EMA), taking it a step closer to being available for patients in the UK. We’re particularly pleased to see this happen, as our scientists played key roles in discovering and developing it.
So what is olaparib, how does it work, and when will it be available here?
A (synthetically) lethal weapon
The principle behind how PARP inhibitors work is known as ‘synthetic lethality’. For classically-inclined readers, this is analogous to targeting cancer’s Achilles’ heel. Or, to put it more bluntly, hitting the disease where it’s vulnerable.
Cancers caused by a faulty BRCA1 or BRCA2 gene have problems with one of the mechanisms that cells use to repair damage to their DNA – a key driver of the genetic chaos that underpins tumour development. As an aside, our researchers played key roles in hunting down BRCA1 and BRCA2 in the 1990s. Despite this flaw they can still struggle along, botching together DNA repairs using an alternative mechanism that depends on a protein called PARP – short for poly-ADP-ribose phosphorylase.
PARP inhibitors, as the name suggests, target PARP in cells and stop it from working. Without this back-up system, the cancer cells have no way of repairing damaged DNA, so they die. Together, the combination of both failures – one genetic, the other due to a drug – is lethal.
This video explains how it works, with the help of some cake and a male model:
The birth of olaparib
Nearly two decades ago, Cancer Research UK-funded scientist Professor Steve Jackson and his team in Cambridge embarked on a mission to find drugs that can block DNA repair pathways, including PARP. Along the way, with help from us and the University of Cambridge, he set up a company – KuDOS Pharmaceuticals – which has discovered and developed a number of promising DNA repair inhibitors over the years.
In 2005, together with Alan Ashworth and his colleagues at The Institute of Cancer Research – also funded in part by Cancer Research UK – researchers showed that these PARP inhibitors could stop cancer cells in their tracks, as long as they also carried a fault in BRCA1 or BRCA2. Tests on BRCA-related tumours in mice gave similar results, while normal, healthy cells seemed to be unaffected – a good sign for any potential cancer treatment.
Then in 2008, researchers at KuDOS published a paper detailing a chemical they named KU-0059436. Not only was it a potent PARP-blocker, but it also had a property that scientists refer to as ‘oral bioavailability’ – meaning that it can be taken as tablets, rather than having to be injected directly into the bloodstream.
AstraZeneca bought KuDOS in 2006, based on the promising lab results, and took KU-0059436 (renamed AZD-2281, and later olaparib) forward through clinical trials for various types of cancer caused by faulty BRCA genes. The results have been variable – at one point the company got cold feet and even shelved the drug – but the most encouraging data emerged from a small phase 2 trial for women with advanced ovarian cancer caused by BRCA gene faults. A phase 3 trial is now under way to make sure these results hold up in a larger study.
Are we there yet?
Today’s positive mod from the CHMP means that olaparib will be taken forward to the next meeting of the EMA in January 2015, where the European experts will have the opportunity to approve the drug formally. That will then give the green light for AstraZeneca to sell olaparib (under the trade name Lynparza) in Europe , for women with advanced serous ovarian cancer, fallopian tube and peritoneal cancer who carry a faulty BRCA1 or BRCA2 gene.
Unfortunately, this doesn’t mean that patients in the UK will be able to have it immediately.
The next step after that is for NICE, the National Institute of Health and Care Excellence, to assess the costs and benefits of the treatment and decide whether to make it available on the NHS in England and Wales. Different organisations will make the decision for Scotland and Northern Ireland.
Right now we don’t know anything about the proposed cost of olaparib, but given the recent disappointing rulings on the prostate cancer drug abiraterone (Zytiga) and breast cancer treatment trastuzumab emtansine (Kadcyla), we are keeping our fingers crossed that AstraZeneca will offer a fair price that the NHS can afford.
It’s also not clear how long NICE’s appraisal might take but it can be many months, so watch this space.
The potential benefits for PARP inhibitors, including olaparib, don’t stop here. Other companies are joining the race to develop their own versions, and over the past few years the research world has been buzzing with discoveries of further potential uses for these exciting drugs. This includes tumours with ‘BRCA-like’ characteristics due to other genetic faults, and cancers that have low oxygen levels.
Olaparib is now being put through its paces in further clinical trials for other diseases, including brain tumours, lung cancer, prostate cancer, oesophageal cancer and pancreatic cancer, plus leukaemia and lymphoma. Other companies are also pushing ahead with trials of their own drugs in a range of cancer types.
It’s clear that the story of PARP inhibitors is only just beginning. In less than a decade we’ve seen one of these drugs go from a twinkle in a medicinal chemist’s eye to being licensed for sale – breakneck pace in the world of drug development. And just five years ago we sat through talk after talk about PARP inhibitors at the NCRI Cancer Conference as researchers excitedly presented data on their future potential.
There are still hurdles to be overcome – not least the potentially thorny issues of NICE approval and pricing – but today represents a significant step forward. We strongly hope that UK cancer patients will soon be able to feel the benefits from olaparib and the other promising drugs coming after it.
Farmer H., et al. Targeting the DNA repair defect in BRCA mutant cells as a therapeutic strategy., Nature, PMID: http://www.ncbi.nlm.nih.gov/pubmed/15829967
Menear K.A., et al. (2008). 4-[3-(4-cyclopropanecarbonylpiperazine-1-carbonyl)-4-fluorobenzyl]-2H-phthalazin-1-one: a novel bioavailable inhibitor of poly(ADP-ribose) polymerase-1., Journal of medicinal chemistry, PMID: http://www.ncbi.nlm.nih.gov/pubmed/18800822