Prof Karim Fizazi - (Department of Cancer Medicine, Institut Gustave Roussey, France)
KM: Thank you Neal. This is the LATITUDE phase III trial which was testing abiraterone and prednisone in patients with de novo metastatic prostate cancer. The data were presented yesterday at this ASCO meeting. Again this is really focussing on patients with de novo metastatic disease. The incidence varies a lot across countries; for example, here in the US it is thought to be around 3% but it’s rising, probably around 6% in Europe and Latin America but if you go to large countries from Asia such as China or India it can rise up to 60% of men who are diagnosed with prostate cancer. So it’s a big thing. As we all know, historically we’ve been using androgen deprivation therapy for these men and this is because it works, at least at the beginning, in almost 100% of them. Having said that, by a year these men have developed resistance to castration, at least for half of them; this is largely driven by reactivation of the AR signalling.
As we probably also all know, the field has changed two years ago and the standard of care has changed, thanks to three randomised trials – GETUG-15, CHAARTED and STAMPEDE – that could establish a role for docetaxel in terms of not only progression free survival but also overall survival with a hazard ratio ranging from 0.73 to 0.88 in overall survival.
LATITUDE was about abiraterone, abiraterone is a CYP17 inhibitor so it’s preventing strongly the making of the androgens, not only from the testes but also the adrenal sources and prostate cancer sources as well. It was a quite straightforward randomisation and we selected patients with de novo metastatic disease who were really at high risk of dying from their disease. High risk was defined as men with at least two of the three high risk criteria: a high Gleason score, more than three bony lesions and visceral metastases. It was a classical phase III trial where men were randomised in a one-to-one fashion to get castration plus or minus abiraterone and prednisone given at 5mg daily or placebos for abiraterone and prednisone. Two co-primary endpoints: overall survival and RPFS. A big, large global trial and docetaxel was not used as a standard of care just because the trial was designed and completed its accrual before the trials establishing the role of docetaxel had read out.
A classical population of patients with metastatic high risk disease, I won’t detail that too much, many of them obviously had bony disease. Most of them had a high Gleason score and actually most of them had many bone metastases. So nasty cancers, obviously. This is the main, most important results about overall survival, one of the key co-primary endpoints. What we saw was a 38% reduction in the risk of death. The median in the control arm was what we were expecting, 34.7 months and it was not even reached in the abiraterone arm with a 30 month median follow-up. So at three years 66% versus 49% overall survival rates.
Across subgroups we saw a real benefit in terms of overall survival. This was true, for example, for patients in good and poor performance status and also, and this is also very important, those with and without visceral metastases. The second co-primary endpoint was radiographic progression free survival and here again, obviously, abiraterone wins. This was a 53% risk reduction in radiographic progression or death; median less than 15 months in the control arm versus 33 months in the abiraterone arm so this was more than twice improved.
This data came together with many other good findings in terms of time to PSA progression, time to pain progression, which is obviously very meaningful, time to symptomatic skeletal events, again very meaningful, and time to chemotherapy, time to subsequent prostate cancer therapy, which are meaningful, not only to patients but also to society in terms of use of resources and cost. Generally speaking, the benefit that we saw was truly related to abiraterone use up front and I’m saying that because most patients in the control arm received life prolonging therapies such as docetaxel, enzalutamide, abiraterone, cabazitaxel, radium-223, actually twice more patients received these drugs in the control arm. So we’re telling that the true benefit we see in overall survival is clearly linked to up front abiraterone.
In terms of safety we basically saw what we already knew from the abiraterone experience which is an excess in hypertension and hypokalaemia, slight excess in transaminase increase, which is really not an issue, and also a slight excess in cardiac disorders.
So, in conclusion, LATITUDE clearly established that for these men with metastatic high risk prostate cancer using abiraterone and prednisone up front significantly improves overall survival with a 38% reduction in risk of death which is obviously just great, and also a significant improvement in radiographic progression free survival. Safety profile was not really an issue, it was really what we were expecting. Based on that, I really believe that we have a new standard of care for these men with abiraterone prednisone being added on top of castration. The data were published yesterday in The New England Journal of Medicine which is just great.
