“The prostate cancer ‘wonder pill’ set to save thousands every year”, read the headline in the Daily Mail today. Widespread media coverage has been given to a trial of a new drug abiraterone, which has indicated that it could successfully treat and prolong the lives of patients with the aggressive and incurable form of prostate cancer. The newspapers said that it could help up to 80% of patients, shrinking their tumours and “end the need for damaging chemotherapy and radiotherapy”. Many of the reports mention that the drug is still in its trial stages and is yet to be proved to have any effect on survival.
The study behind these stories is a preliminary exploration of the safety and tolerability of abiraterone in 21 men with advanced prostate cancer that has not responded to hormone treatments. A second, larger study is reportedly already underway, and if the success of this trial is repeated, it would indicate the drugs effectiveness in treating the disease. The researchers mention in their report that this is an “area of unmet medical need”, and suggest that it could have a rapid route to drug approval.
Where did the story come from?
Dr Gerhardt Attard, Johann de Bono and colleagues from the Royal Marsden NHS Foundation Trust, the Institute of Cancer Research in Surrey, UK and Cougar Biotechnology carried out the study. The research was funded by a grant from Cancer Research UK and by Cougar Biotechnology (manufacturers of abiraterone). The study was published in the peer-reviewed medical journal: Journal of Clinical Oncology.
What kind of scientific study was this?
The study behind the news reports is a phase I (unblinded) trial of a new drug called abiraterone. Abiraterone is a drug that inhibits the action of a chemical (CYP17) in the body, which is involved in the production of hormones (androgen and oestrogen). Phase I studies are conducted to test new drugs very early on in their development, and are usually used to determine the safety, tolerability and appropriate dosage of a new drug for further testing.
In this study, the researchers recruited 21 males with prostate cancer that was resistant to several different hormonal treatments (known as castration-resistant prostate cancer [CRPC]). None of these men had received chemotherapy as a treatment option (chemotherapy is sometimes tried in prostate cancer that is resistant to hormone therapies). All the men were being treated at the Royal Marsden Hospital in the UK, and they knew what treatment they were going to receive in this trial. They initially entered a “wash-out” period (four to six weeks) where they did not take any hormonal treatments – this was to allow previous treatments to be washed out of their bodies. Patients who had abnormal blood potassium or bone marrow, kidney or liver function were excluded, as were those whose cancer had spread to the brain or spinal cord, or those with serious illnesses including uncontrolled high blood pressure, or a history of severe heart failure.
The participants were given daily capsules of abiraterone in 28-day cycles. Doses escalated throughout the study: 250mg, 500mg, 750mg, 1000mg and 2000mg. The researchers recorded any toxic reactions to the treatment and were careful to explore these further when the timing of the reactions corresponded to increasing doses of medicine. The participants were evaluated at the beginning of the study, each week during the first two cycles, and during every cycle thereafter. During these evaluations, they were given physical examinations, and blood tests were taken to determine levels of various factors and compounds. Adverse events were graded according to commonly used criteria. Prostate-specific antigen (PSA - a protein in the blood that is elevated in the presence of prostate cancer) tests were performed at the beginning of the study and after each 28-day dose cycle. Bone and CT scans were performed at the beginning of the study and every three months after. Regular blood samples were taken for hormone testing. Those men who had a measurable tumour had it measured at the beginning of the study and after each treatment.
At the end of the study, the researchers looked at the overall pattern of the men’s response to the new treatment and how their measurements changed over time.
What were the results of the study?
There were no serious treatment-related grade three or four toxic reactions associated with abiraterone (examples of such toxicities are not provided in the report). Response to the drug appeared to level out at a dose of 1000mg daily, so this was the dose chosen for future studies with this drug. Side effects that occurred were controllable. These included high blood pressure, low blood potassium and water retention in the lower limbs, and were caused by the action of excess steroid hormones on the kidney.
There were a number of relevant findings, but in relation to tumour activity, 12 of the 21 patients had a 50% decline in PSA (that was evident after one month and lasted for more than three months). Six of 21 patients had a 90% decline in PSA levels. The researchers also found that in five of the eight patients who had measurable disease at the beginning of the study, partial response was evident (i.e. the tumour shrank).
There was also evidence of regression of some of the cancers that had spread in two patients and a reduction in bone disease (metastases) on CT scan in two others. In 11 patients who had pain and required analgaesics at the start of the study, eight improved to a degree that allowed them to reduce their dose or stop taking analgaesics altogether.
What interpretations did the researchers draw from these results?
The researchers concluded that this is the first study to demonstrate that the continuous inhibition of the CYP17 enzyme is safe and has measurable effects on tumours. The researchers recommend further studies should use a dose of 1000mg daily and that the results of this study have led to a larger (phase II) study in men who have castration resistant prostate cancer. These results “should be reported soon”.
What does the NHS Knowledge Service make of this study?
This early study shows promising results in a small group of men with advanced prostate cancer who have few other treatment alternatives. It is a phase I study, and provides early evidence of the safety and tolerability of abiraterone. However, the results are preliminary, particularly those for efficacy, and no survival advantage has been demonstrated (or explored) in this trial. The study only included 21 men, and it did not compare the treatment with any other options (e.g. chemotherapy) in these participants. The larger study that follows this one will provide more information about the applicability of the treatment to a wider group of people.
Tumour responses here, although significant, occurred in a small number of men. If the results are repeated in larger studies, this drug could be a potentially effective treatment for men with untreatable prostate cancer.
Analysis by Bazian
Edited by NHS Website
Links to the headlines
The Times, 22 July 2008
The Independent, 22 July 2008
The Guardian, 22 July 2008
BBC News, 22 July 2008
Financial Times, 22 July 2008
Daily Mail, 22 July 2008
Daily Mirror, 22 July 2008
Daily Express, 22 July 2008
The Daily Telegraph, 22 July 2008
Links to the science
J Clin Oncol 2008; Jul 21 [Epub ahead of print]
Cochrane Database Syst Rev 2001, Issue 4
Cochrane Database Syst Rev 2006, Issue 4
Cochrane Database Syst Rev 2006, Issue 4