Olaparib (AZD2281), a new type of cancer drug known as a “PARP inhibitor,” produced promising results in patients with platinum-refractory, platinum-resistant, and platinum-sensitive ovarian cancer linked to an inherited BRCA1 or BRCA2 gene mutation.
A new type of cancer drug — known as a “PARP inhibitor” — produced promising results in patients with ovarian cancer linked to an inherited BRCA1 or BRCA2 gene mutation. The trial results were published online in the Journal of Clinical Oncology on April 19th.
Scientists at The Institute of Cancer Research (ICR) and The Royal Marsden Hospital, working with pharmaceutical company KuDOS Pharmaceuticals, now a subsidiary of AstraZeneca, found the experimental drug olaparib shrank or stabilized tumors in approximately half of ovarian cancer patients possessing BRCA1 or BRCA2 mutations.
The five-year survival rate for ovarian cancer is just 40 per cent as the majority of patients are diagnosed with an advanced form of the disease. Most patients initially respond well to radical surgery and platinum and taxane-based chemotherapy, but relapse after an average of 18 months. Subsequent treatments generally become less effective as patients build up resistance.
“There is an urgent need to find new drugs for women diagnosed with ovarian cancer,” says Professor Stan Kaye, Head of the Section of Medicine at the ICR and Head of the Drug Development Unit at The Royal Marsden Hospital and a Cancer Research UK-funded scientist. “Olaparib is still in early-stage testing but the results so far are very encouraging. These findings raise the possibility that carefully selected patients in future may well be offered olaparib as an alternative to chemotherapy during the course of their treatment.”
Between 2005 and 2008, about 50 women with confirmed or suspected BRCA1 or BRCA2 mutations began treatment with olaparib in a dose escalation and single-stage expansion of a Phase I trial. Twenty patients responded with their tumors shrinking or with significant falls in their ovarian cancer marker CA125, or both. The disease also stabilized in three patients. The drug was effective for an average of seven months. Notably, several patients are still taking olaparib (for nearly two years). Drug side-effects were generally mild, especially when compared to current chemotherapy treatments.
Olaparib is a new type of drug known as a PARP inhibitor that works by turning a tumor’s specific genetic defect against itself. In susceptible cells, olaparib prevents the repair of naturally occurring breaks in DNA, which healthy cells are able to repair. Susceptible cancer cells – those with an existing defect in a DNA repair pathway caused by a mutation in the BRCA1 or BRCA2 genes – are unable to repair themselves, and therefore, die.
Platinum-based chemotherapy, particularly carboplatin, is one of the main treatments used for ovarian cancer. When this treatment ceases to be effective, theoretically, olaparib might be less effective too, so the ICR scientists examined whether olaparib would still benefit patients whose response to previous platinum-based drugs was limited. Finding new drugs to treat these “platinum-resistant” ovarian cancer patients (those who relapsed within six months of previous platinum therapy) is a particularly high priority as they have a lower chance of benefiting from re-treatment with chemotherapy and a poorer prognosis.
The research team found that the clinical benefit rate with olaparib was indeed higher — 70% — among patients with “platinum-sensitive disease” (disease recurrence more than six months after previous platinum therapy). Crucially, however, the clinical benefit rate was still 46% in platinum resistant patients.
ICR Study Findings:
- 50 patients participated in the study (13 had platinum-sensitive disease, 24 had platinum-resistant disease, and 13 had platinum-refractory disease (according to platinum-free interval).
- 20 patients (40%) achieved complete or partial responses under RECIST (Response Evaluation Criteria in Solid Tumors) criteria and/or tumor marker (CA125) responses.
- 3 patients (6.0%) maintained RECIST disease stabilization for more than 4 months.
- Overall clinical benefit rate (complete response + partial response + stable disease) = 46%.
- Median response duration was 28 weeks.
- There was a significant association between the clinical benefit rate and platinum-free interval across the platinum-sensitive, resistant, and refractory patient subgroups (69%, 45%, and 23%, respectively).
- Analyses indicated associations between platinum sensitivity and extent of olaparib response.
- CONCLUSION: Olaparib has antitumor activity in BRCA1/2 mutation ovarian cancer, which is associated with platinum sensitivity.
Up to 15 per cent of breast and ovarian cancers have known BRCA1 or BRCA2 mutations on blood testing and, importantly, laboratory data strongly suggests that olaparib may also be effective in cancers linked to DNA repair defects not caused by BRCA1 and BRCA2 mutations. This could apply in about half the cases of the most common histological type of ovarian cancer.
“We have good reason for thinking that the benefit seen with olaparib in BRCA mutation-linked ovarian cancer may well extend to a broader population of patients with this disease,” says Professor Kaye.
Randomised trials of olaparib – in which some patients receive the drug and others a placebo – are underway and results will be available later this year.
KuDOS Pharmaceuticals (a wholly owned subsidiary of AstraZeneca) was the major funder of the trial, along with Cancer Research UK and the National Institute for Health Research. Olaparib was identified and developed at KuDOS Pharmaceuticals and subsequently at AstraZeneca.
PARP Inhibitor Clinical Trials:
To view a list of open ovarian cancer clinical trials that are testing olaparib (AZD2281), click here.
To view a list of open solid tumor clinical trials that are testing olaparib (AZD2281), click here.
To view a list of open ovarian cancer clinical trials that are testing various PARP inhibitors, click here.
To view a list of open solid tumor clinical trials that are testing various PARP inhibitors, click here.
About The Institute of Cancer Research (ICR)
* The ICR is Europe’s leading cancer research centre.
* The ICR has been ranked the UK’s top academic research centre, based on the results of the Higher Education Funding Council’s Research Assessment Exercise.
* The ICR works closely with partner The Royal Marsden NHS Foundation Trust to ensure patients immediately benefit from new research. Together the two organisations form the largest comprehensive cancer centre in Europe.
* The ICR has charitable status and relies on voluntary income, spending 95 pence in every pound of total income directly on research.
* As a college of the University of London, the ICR also provides postgraduate higher education of international distinction.
* Over its 100-year history, the ICR’s achievements include identifying the potential link between smoking and lung cancer which was subsequently confirmed, discovering that DNA damage is the basic cause of cancer and isolating more cancer-related genes than any other organization in the world.
* The ICR is home to the world’s leading academic drug development team. Several important anti-cancer drugs used worldwide were synthesised at the ICR and it has discovered an average of two preclinical candidates each year over the past five years.
For more information visit www.icr.ac.uk.
About The Royal Marsden Hospital
The Royal Marsden opened its doors in 1851 as the world’s first hospital dedicated to cancer treatment, research and education. Today, together with its academic partner, The Institute of Cancer Research, it is the largest and most comprehensive cancer centre in Europe treating over 40,000 patients every year. It is a centre of excellence, and the only NHS Trust to achieve the highest possible ranking in the Healthcare Commission’s Annual Health Check for the third year in a row. Since 2004, the hospital’s charity, The Royal Marsden Cancer Campaign, has helped raise over £43 million to build theatres, diagnostic centres, and drug development units. Prince William became President of The Royal Marsden in 2007, following a long royal connection with the hospital.
For more information, visit www.royalmarsden.nhs.uk
About Cancer Research UK
* Cancer Research UK is the world’s leading charity dedicated to beating cancer through research.
* The charity’s groundbreaking work into the prevention, diagnosis and treatment of cancer has helped save millions of lives. This work is funded entirely by the public.
* Cancer Research UK has been at the heart of the progress that has already seen survival rates double in the last thirty years.
* Cancer Research UK supports research into all aspects of cancer through the work of more than 4,800 scientists, doctors and nurses.
* Together with its partners and supporters, Cancer Research UK’s vision is to beat cancer.
For further information about Cancer Research UK’s work or to find out how to support the charity, please call 020 7121 6699 or visit www.cancerresearchuk.org
About Experimental Cancer Medicine Centre (ECMC)
Experimental Cancer Medicine Centre (ECMC) status has been awarded to 19 centres in the UK that are specialist centres conducting research into new cancer treatments. The aim is to bring together cancer doctors, research nurses and lab scientists to make clinical trials of new treatments quicker and easier. The ECMC initiative is funded by Cancer Research UK and the Departments of Health of England, Scotland, Wales and Northern Ireland. Together they are giving a total of £35 million pounds over five years to the 19 centres. The centres will use this money to run trials of new and experimental treatments. They will also analyse thousands of blood and tissue samples (biopsies) to help find out more about how treatments work and what happens to cancer cells.
- Drug Benefits Patients with Inherited Ovarian Cancer, News Release, The Institute of Cancer Research, April 20, 2010.
- Fong PC, Yap TA, Boss DS, et. al. Poly(ADP)-Ribose Polymerase Inhibition: Frequent Durable Responses in BRCA Carrier Ovarian Cancer Correlating With Platinum-Free Interval. J Clin Oncol. 2010 Apr 20. [Epub ahead of print] PubMed PMID: 20406929.