The Daily Telegraph reported today on a new drug that could “shrink inherited breast and ovarian cancers”. It said that the drug, called olaparib, targets cancer cells caused by faulty genes and that researchers have found it could shrink tumours in 40% of advanced breast cancer patients and in a third of those with advanced ovarian cancer.
The news report is based on two small phase 2 studies of this new drug for treating women with advanced cancer. Both studies demonstrated that tumours responded to both a 400mg twice-daily dose and a 100mg daily dose, given for 24 weeks. There were some side effects associated with treatment, mainly nausea and fatigue.
This is promising research but is at an early stage and the drug’s effectiveness will need to be proven in larger, longer trials. These trials will need to compare the effects of the new treatment with other currently available drugs and to no treatment, and monitor important outcomes, such as overall survival.
Where did the story come from?
These studies into the new drug olaparib were carried out by researchers from King’s College London, the Samuel Oschin Cancer Institute in Los Angeles, the Memorial Sloan-Kettering Cancer Center in New York, and other academic and medical institutions across the world.
The work was funded by AstraZeneca; the manufacturer of olaparib. It was published as two separate research papers in the peer-reviewed medical research journal The Lancet with different lead authors, one focusing on the breast cancer study and the other on the ovarian cancer study.
The newspapers have reported this research well, and although none go too deeply into the methods of the studies, all rightly report that this is early stage research and clinical trials are necessary before it can be licensed as a treatment for breast or ovarian cancers.
The Daily Mail reports incidence rates for the inherited forms of the cancer, saying that around 3% of the 46,000 women diagnosed with breast cancer and 10% of the 7,000 new cases of ovarian cancer every year are inherited forms.
What kind of research was this?
BRCA1 and BRCA2 are genes that are involved in the healthy repair of DNA. Women who have mutations in these genes may be more susceptible to breast and other cancers. If there is a strong family history of breast cancer, then faulty BRCA1 and BRCA2 genes may be responsible as these mutations can be inherited.
Olaparib is a drug that can inhibit an enzyme called PARP-1 (poly [ADP-ribose] Polymerase). PARP-1 plays a role in inhibiting the normal repair of DNA and is therefore thought to be linked to BRCA1 and BRCA2 mutations, causing cancer in humans.
This research consisted of two phase 2 studies of cohort design, each looking at the effect of the drug olaparib on breast and ovarian cancer. Phase 2 trials are early research and usually followed by larger, randomised phase 3 trials. In these two studies, women who had a confirmed BRCA1 or BRCA2 mutation and either confirmed breast or confirmed ovarian cancer were enrolled from across different centres in Australia, Germany, Spain, Sweden, the UK and the US. The methods for each study were similar and are described below.
What did the research involve?
The breast cancer study enrolled 54 women from 16 treatment centres with metastatic breast cancer, or confirmed harmful BRCA1 or BRCA2 mutations and locally advanced cancer not amenable to curative surgery or radiation. All women had one or more tumours that could be measured according to the RECIST criteria (Response Evaluation Criteria In Solid Tumours). This is a simple way of determining the response of a tumour to a treatment. They had also all had at least one chemotherapy regimen and at least one regimen of hormone therapy if the cancer was hormone receptor positive, and an estimated life expectancy of at least 16 weeks.
Women with particular characteristics were not included, including those that had taken any anticancer drugs in the last 28 days, those with toxicities caused by previous therapies and those with progressive or symptomatic metastases in the brain or central nervous system.
The women with breast cancer were sequentially assigned to two separate cohorts: 27 women in the first who were given continuous oral olaparib at a maximum dose (400mg twice daily), and a second cohort given a lower dose of 100mg twice daily. The women were given the drug for about six months continuously, with assessments at the end of every 28 days.
The ovarian cancer study enrolled 57 women from 12 centres. All were over 18 years and had a form of ovarian cancer (recurrent epithelial ovarian cancer, primary peritoneal or fallopian tube carcinoma that had come back after a previous regimen of chemotherapy). They also had one or more measurable lesions according to the RECIST criteria and a life expectancy of 16 weeks.
Other types of chemotherapy, endocrine therapy, antibody-based therapy, or high-dose radiotherapy were not permitted during the study or for 28 days before the study started. Some women were excluded, including those with brain or CNS metastases that were progressive or symptomatic within 28 days of starting study treatment, or a history of any other malignant disease in the last five years or toxicities caused by a previous treatment.
As in the breast cancer study, the women with ovarian cancer were assigned to two separate cohorts: 33 to the 400mg twice-daily group and 24 to the 100mg twice-daily group. Drugs were given in 28-day continuous cycles.
The primary outcome for both studies was objective tumour response rate (ORR) according to the RECIST criteria; this is how many patients had a complete or partial response to treatment. This method is widely used in trials and defines tumour shrinkage or progression according to a measurement of a single isolated lesion. Responses were assessed after at least 28 days with a CT scan and RECIST criteria.
The researchers also assessed how many breast cancer patients had a complete or partial response or who had stable disease for at least 23 weeks, progression-free survival and duration of response, as well as drug safety. Ovarian cancer patients were also assessed for progression-free survival, clinical benefit rate and if the drug had a complete or partial response (that is, if it stopped the tumour growing again and, if so, for how long). The number of women with complete or partial response or stable disease for 15 weeks or more was also analysed.
What were the basic results?
In the breast cancer trial, olaparib was demonstrated to have an objective response in 41% (11/27) of those given 400mg and 22% (6/27) of those given 100mg. Of these, one patient in the 400mg group had a complete response compared with no patients in the 100mg group. Disease progressed in four patients (15%) in the 400mg group and nine patients (33%) in the 100mg group. Both doses were associated with stable disease for at least 23 weeks in 12 (44%) women.
For women with ovarian cancer, 11 (33%) who were taking 400mg twice daily showed a partial or complete response. In the group taking 100mg twice daily, three patients (13%) showed a partial or complete response.
The most common side effects in both studies were nausea and fatigue.
How did the researchers interpret the results?
For both studies, the researchers conclude that their results provide positive proof of concept; that is, that a drug that can inhibit PARP can have anti-tumour effects in people with BRCA1 and BRCA2 tumours.
The results from these phase 2 studies are promising and demonstrate some tumour response to olaparib. Many women did not complete the full course of treatment, but this is expected in these types of trial. In the ovarian cancer trial, 33 of 57 (57%) of women taking either dose stopped taking the drug mainly because of disease progression and only 29 of the 54 (54%) women in the breast cancer trial completed six cycles of 28 days continuous treatment.
Importantly, these are early studies of a new drug and their results must be considered in this context. The main point to bear in mind is that these studies did not have a comparator group, and so did not compare the effectiveness of the drug to no treatment or to other drugs.
Such comparative studies are necessary to determine whether a new treatment is better than nothing or better than current practice. Such phase 3 studies usually follow phase 2 studies like these ones, and could be expected to be randomised controlled trials of longer duration with more recruits and monitoring important outcomes, such as overall survival.
It is also important to remember that the results from this trial may not apply to all women with inherited cancers. Those in the studies were a select group, all with relatively severe disease that had been previously treated by at least one chemotherapy regimen.