“A new way of treating cancer has shown ‘great promise’ in its first clinical trial,” the Financial Times reported. The newspaper said that the drug, olaparib, has undergone its first clinical trial in humans and is showing “impressive” results in treating advanced cancers. So far, it has been given to 60 patients with genetically inherited breast, ovarian and prostate cancers, but the researchers are planning to carry out more extensive clinical trials to discover how effectively the drug will fight other cancers.
This phase 1 clinical trial was well conducted and designed. It demonstrates a new approach to treating some genetically inherited cancers (BRCA1 and BRCA2 cancers). The drug appears to target only cancer cells that carry a mutated gene and not healthy cells. This is early research and it is not yet known how effective the drug is for long-term survival. Future randomised trials will be followed with interest.
This research was conducted by Dr Peter C Fong from the Royal Marsden NHS Foundation Trust and the Institute of Cancer Research, and colleagues from other Breakthrough Breast Cancer Research Centres and Cancer Institutes in the UK and the Netherlands.
The study was supported by KuDOS Pharmaceuticals, a wholly owned subsidiary of the pharmaceutical company AstraZeneca. The research was also partly funded by a programme grant from Cancer Research UK, the Experimental Cancer Medicine Centre and the National Institute for Health Research Biomedical Research Centre.
The New England Journal of Medicine, a peer-reviewed medical journal, published the paper.
This was a phase 1 clinical trial of a new drug, olaparib. The aim of the trial was to determine the drug’s safety, report adverse events and toxicity and look for the maximum tolerated dose of the drug using blood and tissue samples.
Olaparib inhibits an enzyme called poly(adenosine diphosphate ribose) polymerase (PARP) and is a new class of drug known as a PARP-inhibitor. The PARP enzyme repairs DNA and is found in the nucleus of cells.
The researchers explain that the drug works on cancers with specific DNA-repair defects, such as the cancers in people who carry a BRCA1 or BRCA2 mutation in their genes. Mutations of the BRCA1 and BRCA2 genes weaken the body’s ability to repair DNA damage. BRCA1 and BRCA2 mutations are responsible for about 5% of breast cancers and cause particularly aggressive tumours. The same mutations are also found in some ovarian and prostate cancers.
The new drug kills cancer cells through a process called synthetic lethality. In this process, only cancer cells are harmed as healthy cells can repair their DNA using alternative pathways. The DNA in cells is continually subject to damage. To ensure the cells’ survival, there are several coordinated pathways which repair the damaged DNA. The PARP enzyme repairs DNA single-strand breaks through a process called base excision. When PARP is inhibited, there is an accumulation of DNA single-strand breaks, which can lead to DNA double-strand breaks. These breaks are repaired by another double-stranded DNA repair pathway, the key components of which are the tumour-suppressor proteins BRCA1 and BRCA2. It is only if both pathways are affected that the cancerous cell dies.
The researchers enrolled a group of 60 patients, who were at least 18 years old, with cancer that had come back after standard therapies or for which there was no suitable effective standard treatment. Of these, 22 were carriers of a BRCA1 or BRCA2 mutation and one had a strong family history of BRCA-associated cancer but declined to undergo mutational testing. All patients were generally active and had functioning bone marrow with good liver and kidney function. A gap of four weeks was left after previous anticancer therapy for a “washout period”.
Although 60 patients were enrolled, the researchers only included the 22 patients who were carriers of BRCA1 or BRCA2 mutations. Patients were initially given a 10mg dose of olaparib once a day for two of every three weeks. This dose was subsequently increased to 60mg, twice daily, and then further increased to up to 600mg twice daily, given continuously. Adverse events were graded one to five according to the Common Terminology Criteria for Adverse Events, where one is a mild event, like transient flushing, and five is death. The dose was increased according to a protocol, such as a doubling of the dose in the absence of adverse effects of grade two or higher during that cycle. In this way, the researchers estimated toxicity of the drug at a given dose. The dose was considered the maximum that could be administered if two signs of dose-limiting toxicity were observed during the first treatment cycle. A drug-related adverse effect of grade three or four occurring in the first cycle was considered a sign of dose-limiting toxicity. In other words, this was the top dose and was not increased.
Samples of peripheral-blood mononuclear cells (a type of white blood cell), plucked eyebrow-hair follicles, and tumour tissue were tested for antitumour response.
Safety evaluations were conducted at the beginning of the trial and afterwards at weekly visits. Each evaluation consisted of the patients’ history being taken, a physical examination, laboratory tests, including a complete blood count, levels of clotting factors and electrolytes, liver- and renal-function tests, and an electrocardiographic tracing.
The olaparib dose and schedule were increased from 10mg daily for two of every three weeks to 600mg twice daily continuously. Five patients managed to get to this top dose.
Reversible dose-limiting toxicity (temporary toxic side effects of the drug) was seen in one of eight patients receiving 400mg twice daily (grade three mood alteration and fatigue) and two of five patients receiving 600mg twice daily (grade four thrombocytopenia and grade three somnolence). Other adverse effects included mild stomach upset.
When the researchers tested the anti-cancer properties of the drug by examining the tissue samples, the results confirmed inhibition of the PARP enzyme.
This objective antitumour activity was reported only in mutation carriers, all of whom had ovarian, breast or prostate cancer and had received multiple treatment regimens.
The researchers say that olaparib has few of the adverse effects of conventional chemotherapy. It inhibits PARP and has antitumour activity in cancer associated with the BRCA1 or BRCA2 mutation.
Creating drugs that selectively kill cancer cells without harming normal cells is notoriously difficult. This phase 1 trial indicates that olaparib might be able to do this. The researchers have shown that the drug can selectively kill cancer cells by targeting the DNA repair mechanisms in cancer cells that carry two specific oncogenes (mutated forms of genes involved in the process that causes normal cells to become cancer cells).
As with all early non-randomised studies conducted in small numbers of people, care must be taken not to prematurely build up expectations of the drug’s effectiveness. Some cautions:
Overall, this well-conducted study appears to demonstrate a new approach to treating the BRCA1 and BRCA2 cancers and the drug’s future will be observed with interest.