When we develop drugs for prostate cancer, for disease that has metastasised, we’ve done it in patients whose disease has grown with a suppressed testosterone, so castration resistant disease is the term we use. Docetaxel was the first drug to show a benefit increasing the longevity of a man who has castration resistant disease by about two months when we use the median overall survival endpoint. Here we said if it works in the late stage disease will it work better if we use it when we start the testosterone suppression for the first time.
What did you do in the study?
So we identified men who had metastatic disease for the first time, disease that had spread from their prostate gland to their bones or their liver or their lungs but some men had had a prior local treatment and it had spread, other men it had presented into their... they’d presented for the first time with metastatic disease, telling us that they had prostate cancer. So we had both groups of patients.
Half the men were randomised to the standard treatment and the standard treatment we’ve been using for seventy years of suppressing the testosterone, also known as androgen deprivation therapy. The other half of the patients that were enrolled got six cycles of docetaxel chemotherapy with the testosterone suppression and then stopped and then they were followed until their cancer progressed and until they died. We found there was a significant improvement in the overall survival and, I would say, a clinically meaningful improvement.
What is the significance of this discovery?
So there are two things. The chemotherapy is not viable for every patient, some patients are too frail, and those drugs, those hormonal therapies that are better tolerated, are more applicable to more patients. However, we do know that in this case an approach that attacks the cancer cells in different angles, so going after different pathways at the same time, was more effective than just going after the androgen receptor alone in this case.
What about the volume of disease and its extent?
Most of the patients who were accrued to this ended up having a high volume of disease which we defined as a patient who had four or more bony metastases with one at least beyond the vertebral bodies or the pelvis, or disease in the liver or lungs which we’ve known for years that these patients do poorer. So we looked at them specifically and showed that the early outcome, the benefit is seen greatest in them. So the improvement in median survival goes from 32 months to 49 months. Patients with lower volume of disease tend to live a longer time and we need longer follow-up to see if there is a benefit in that patient population.
Why haven’t we been using this approach until now?
The answer is we didn’t have the data. There was a lot of speculation as to why it wouldn’t work and there was a lot of speculation as to why it would work. So we needed to design a study with a specificemphasis on those who had high volume disease to answer the question. So we did that and because the timelines are longer than they are for castration resistant disease we need groups like the EasternCo-operative Oncology Group, the National Cancer Institute’s support to do these studies and various countries around the world which have their own government supported work – the UK and CR-UK does great work, MRC is doing a similar study. So we need groups that have a different agenda than what industry has.
Were these studies federally funded?
I would say that it is a fantastic justification for tax-payer dollars being invested in cancer research through this mechanism, and donor money as well through CR-UK and the MRC support and the EORTC and other co-operative mechanisms throughout the world. That’s because our needs for our patients often take a longer time to be defined and answer the questions and that basically can sometimes be beyond the patent life of a drug. That’s why there’s a partnership between industry, physicians, patients and the whole world to answer these questions.
What steps did you take to ameliorate the effects of docetaxel’s toxicity?
We do need to balance the treatment burden against the benefit. There were no surprises from the toxicity profile from docetaxel. 6% of patients did end up with a significant infection with a lowered white cell count from the bone marrow side effect of docetaxel. 1% had got impairments of their nerves that may affect their ability to do up their buttons and oftentimes that’s reversible. We do have an analysis planned where we’re going to measure the quality of life so we can balance the treatment burden against the survival benefit.
What are the clinical implications that oncologists should take note of?
They should offer this chemotherapy with six cycles of docetaxel when starting testosterone, especially for men with high volume disease but you have to match the treatment to the patient and are they fit for chemotherapy. So when they’re starting their testosterone suppression, six cycles of chemotherapy with docetaxel and then stop, especially if they have a high burden of disease and they can tolerate chemotherapy.
What is the take away message for doctors?
We have evidence of benefit of docetaxel with hormonal therapy when a man is starting his hormonal therapy for metastatic prostate cancer.