Author:

Camilla Fiz

Abstract

In the early 2010s, many European centres joined forces to form the Prostate Cancer Consortium in Europe (PEACE) to carry out phase 3 trials in prostate cancer field. After about 10 years, 7 projects, PEACE-1 is now the first trial of the PEACE programme to be completed that has put into the market the triplet therapy for patients with metastatic prostate cancer. Karim Fizazi is a medical oncologist at the Gustave Roussy Institute, which funded PEACE with his colleagues and worked on the PEACE-1 trial. He did this in years when the prostate cancer scientific community was not accustomed to working together across Europe.

Prof. Karim Fizazi interviewed by Camilla Fiz

Today, prostate cancer is the second most common cancer among men worldwide. However, its overall survival after 5 years after the diagnosis has increased, while the mortality has drastically decreased in the last year. In 2015, you and your colleagues wrote in the first PEACE milestone paper that these improvements were mostly related to earlier diagnosis and phase 3 clinical trials. After almost 10 years, do you still agree with this statement?

Actually, their roles are even more important now than they were 10 years ago. We have probably made more progress in curing prostate cancer in the last decade than in the previous 50 years. There has been a fantastic decay in mortality and a big part of those progresses is related to academic phase 3 trials that were conducted, either in Europe, North America, or Australia-New Zealand. One of the major achievements in the last decade has been using earlier the second-generation hormonal agents. When they were first tested 15 years ago, in later stages, they improved outcomes for all survivors by just three months or so in median. But then, progressively, they were moved earlier in the course of the disease. The benefit to patients is now in years and years, either in metastatic castration-sensitive disease, or even earlier in high-risk localised disease. Other examples include the understanding of the role of hormone-chemotherapy or the radiotherapy combinations, as shown so far by the PEACE-1 trial. Treatments are also getting even more individualized. We can sequence cancers to identify people with tumoral alterations, such as BRCA, whose prognosis can be tremendously improved by targeted drugs.

When and why have things started changing in the field of phase 3 clinical trial in prostate cancer treatment?

It started about 25 years ago when we decided together to join forces here in France, and then on a larger scale 10 years ago with PEACE. Prior to this period, from the 1980s to the early 2000s, some research centres in Europe were running trials, but the largest countries were not necessarily involved and committed. Phase 3 clinical trials were conducted in the United Kingdom, in Scandinavia and within the European Organisation for Research and Treatment of Cancer (EORTC)](@eortc), but they were scarce in my country in France, nor in Spain, in Germany and in Italy.

An example of fragmented research in the early 2000s could be the case of hormone-chemotherapy for metastatic prostate cancer patients, to which you directly collaborated. Several centres began testing it, but a certain point the results seem to be conflicting. What happened?

In the early 2000s, more or less at the same time, three research groups had the same idea. In France, we launched the GETUG-12 trial in high-risk localized disease and the GETUG-15 trial in metastatic disease, in England there was the STAMPEDE trial, while in the United States the CHAARTED trial. The original idea was to combine docetaxel chemotherapy to Androgen Deprivation Therapy (ADT), the standard hormonal treatment for men with metastatic prostate cancer. Unfortunately, these three research groups didn’t really speak to each other, and even didn’t necessarily know that the others were doing and planning these trials. Our GETUG-15 trial in France read out first, but it was the smallest, also for financial reasons. When the trial was designed in the early 2000’s, our research group was not strong enough to consider conducting a trial with thousands of patients. Thus, we enrolled fewer than 400 men that were enough to demonstrate improvements in Progression Free Survival (PFS) in men treated with the hormone-chemotherapy, but not enough to show an increase in Overall Survival (OS), as compared to those treated just with ADT. [Editor’s note: PFS and OS are markers of an effective treatment. It is crucial to test both in phase 3 trials before a treatment is approved by drug regulatory bodies, such as the European Medicines Agency (EMA), and introduced into the market.] A year later, the CHAARTED trial came out with twice as many patients, then showing that adding docetaxel chemotherapy doesn’t improve only PFS, but also OS. Another year later, these outcomes were further confirmed by the STAMPEDE trial in the United Kingdom. After these results, the hormone-chemotherapy was introduced into clinical practice for men with metastatic prostate cancer as a new standard of care. It was only then that we realised that we were all doing the same thing and that these findings were all leading to a therapeutic improvement for these patients.

It was indeed getting clear that a new way of doing research in this field was required. Whas this the idea behind the PEACE project?

The main goal of this programme was to make things easier, also taking into account the failures and limitations of the previous research centre’s consortium, involving money or structural problems. An example was the EORTC, that had been very important in oncology for making academic centres to work together in the 1980s and 1990s, when international collaboration was very difficult. At this time, for political reasons, having Eastern Europe working with Western Europe was obviously a major challenge. Also, the Euro didn’t exist, all the money were different, and you needed a passport to cross the borders in Europe. EORTC made a great work in this context, though at the end of the 2000’s significantly less trials were conducted by this group for genitourinary cancers. That emphasized the need for a new and perhaps more flexible system. One limitation may have been that a large part of the budget had to be used for fixed costs of a research entity, and not directly to support a funded trial. Learning from that, I felt that we should invent an easier and smoother concept, with basically no or limited such financial need. The big difference is indeed that in PEACE all the budget goes for the trials.

In conceiving PEACE, have you been inspired by other projects?

I think it was a new idea, even if it hasn’t been the first consortium at all. In the United States, for example, there are clinical trials cooperative, but the PEACE programme was probably the first consortium to bring together research centres from different countries in a virtual format.

How was the PEACE project born?

It was born almost in 2014, when I was already the head of the Department of cancer medicine at the Gustave Roussy Institute. There were several meetings, where several colleagues and I were sitting from different countries in Europe, speaking about how to improve the phase 3 clinical trials in prostate cancer research. At some point I had the idea of launching the PEACE programme, I presented the concept at a meeting and managed to convince my colleagues to join it. Just to start, I asked the group leaders to help me to summary all the European contributions to the field of prostate cancer research. I thought it was interesting to know what Europe was able to do, before introducing what’s next. Then we put in words all this information and the concept of the consortium in a paper published in 2015 in the journal European Urology. Over those meetings, we also gave ourselves some rules: the project has to be European, but open to other countries, even to small and very motivated research centres. There have to be at least two European countries joining forces, but of course more was better. The money can come from various sources, such as taxes, or charities, or pharma. There should be a chairperson who’s spending time making a trial out of the ground. Also, specific rules ensure that the publications are fair to everyone’s contributions. I think that these points have been part of the success of PEACE. Now, 10 years after, we’re talking about producing another paper to summarize what we have done in the last decade.

**Over these initial meetings you also decided that PEACE-1 referred to men with metastatic prostate cancer would have been the first trial of the programme. What has been the PEACE-1 contribution? **

Before 2015 men with metastatic prostate cancer were treated with one drug, the hormonal approach of Androgen Deprivation Therapy (ADT). However, it wasn’t effective on its own in most patients for a long time, thus we progressively moved from one to two drugs, combining ADT to docetaxel. Indeed, around 2015 the GETUG-15, the CHAARTED and the STAMPEDE trials came out changing the standard therapeutical approach of these patients. Some years later, this was drastically modified again by the PEACE-1 trial, showing that three drugs are better than two in treating men with metastatic prostate cancer. Indeed, its previous results were conceived at the ESMO conference in 2021, and then published in The Lancet in 2022. They showed that the so-called triplet therapy, that includes ADT, docetaxel and abiraterone, an Androgen Receptor Pathway Inhibitor (ARPI), could improve both PFS and OS. Last year it came out the second biggest achievements of PEACE-1, that is likely going to change again the clinical practice of these patients. In this case, we were able to show that radiation therapy in men with metastatic disease prevents local symptoms in the long term when the cancer progresses.

From a biological viewpoint, why are three drugs more successful than two and one in these patients?

The reasons are many. When we showed that two is better than one, it’s probably because we’re using two different mechanisms of actions. The first line was hormone therapy, which restricts the androgen production fuelling the prostate cancer development, while the second one was chemotherapy with docetaxel, a taxane that prevent cancer cells from dividing and growing. They indeed involve different mechanisms that are probably synergistic and arm the cancer by two different weapons. Instead, the passage from two to three drugs uses two agents targeting better the main oncogenic driver of the disease, which is the androgen receptor pathway. In this way, with three drugs we are using two hormonal agents instead of just one, blocking the androgen production in different ways.

More drugs often mean higher costs. Have there been problems in terms of triplet therapy’s sustainability and accessibility?

This happened in the past, but I think things are changing now that ADT, docetaxel and abiraterone have gone generic and the cost has come down dramatically. However, this is not always the case, as with other triplet therapies using enzalutamide or darolutamide. Darolutamide is an ARPI which was shown to be effective in metastatic prostate cancer the next year after PEACE-1, but it is much more expensive than abiraterone. Thus, having access to a cheaper drug can be of foremost importance especially in low-income countries.

But PEACE-1 was only the first of a long series of PEACE trials, isn’t it?

Together with PEACE-1, the PEACE-2 trial was established at the beginning with the aim to test cabazitaxel, a chemotherapy, and also radiation to the pelvic lymph nodes in patients with very high-risk localized prostate cancer. This trial has completed its accrual, and we’ll probably carry out the analysis in 2025. Besides this, we have launched 7 PEACE trials aimed to improving the prognosis of men with prostate cancer at different disease stage and by different perspectives. Whether PEACE-1 involved men with metastatic prostate cancer still sensitive to the hormonal therapy of ADT, PEACE-3 and 4 are referred to those resistant to hormonal therapy, at the so-called Castration Resistant Prostate Cancer phase. Moreover, PEACE-6 is a platform of three (and hopefully soon four) phase 3 trials which will test various treatments in various populations of men with metastatic prostate cancers. It includes for example those who are typically too sick to be included in clinical trials, those with oligo-metastatic disease, or those with an unfavorable response after several months of therapy. Besides all these projects, we are also planning to soon open PEACE -7 and -8.

After more than 10 years of PEACE and 8 clinical trials launched, have the initial statements been confirmed over time?

Most of what we were hoping to do has been successful. Firstly, the programme as a whole has enrolled more than 3.000 patients, far more than any single trial before. Secondly, some of these trials have already produced positive results and changed practice, we previously mentioned the triplet systemic therapy. Thirdly, if you look at PEACE-1, it has involved 77 hospitals in France, Italy, Belgium, Romania, Ireland, Spain and Switzerland, countries that had not worked together in the past. Fourthly, we’re more collaborating between research groups and speaking one to the other, preventing from useless competition. For example, the STAMPEDE group in the United Kingdom decided to test the role of metformin in a randomized clinical phase 3 trial. To avoid repetition, and after discussion with them, we decided not to do the same trial, but to focus on statins and aspirin in PEACE-4.