Karim Fizazi, MD, PhD, reviews darolutamide data in prostate cancer, including data from phase II clinical trial, ODENZA.
Karim Fizazi, MD, PhD: ODENZA is a trial including 250 men approximately, and this is a patient preference trial. These men were randomized to receive either darolutamide or enzalutamide first for 3 months and after this time, patients were switched to the other drug, so either [enzalutamide] first and [darolutamide] second, or [darolutamide] first and [enzalutamide] second.
The primary end point of the trial was to assess patients’ preference between the 2 agents after the second period of time, when patients had received approximately 6 months of therapy. Based on what patients reported to us through a self-filled questionnaire, approximately 50% of men preferred darolutamide, 40% of men preferred enzalutamide, and 10% didn’t have a preference between the 2 agents. The main reasons patients preferred darolutamide were about fatigue and quality of life maintenance. The rest was released at ASCO [American Society of Clinical Oncology annual meeting], and hopefully we will have a paper out soon.
At ESMO [European Society for Medical Oncology] more recently, we updated the analysis by looking at cognitive impairment assessments during the time of the trial. In the trial, we asked the patient to answer some questions using the COGSTATE [cognitive assessment using computerized cognitive tests] methodology. This is based on tablets, and you are asking questions to patients at baseline and then 3 months later when they have been exposed to either darolutamide or enzalutamide. We found that memory seems to be more impaired with enzalutamide compared to darolutamide. This was true in terms of the process of memory and especially for immediate memory, which was more impacted with enzalutamide as compared to darolutamide, mostly what we call episodic memory.
Some trends favor darolutamide regarding better attention and executive functions, which are different aspects of cognition that we assessed in the trial. Memory was impaired more with enzalutamide, the acquisition of new information as well as the recall of the same information after a brief delay. That basically confirmed our clinical feeling that enzalutamide was actually harming memory in some men, while darolutamide doesn’t seem to have the same adverse effects. For the first time, we were able to assess objectively something we thought was existing subjectively because of what the patients or their families were telling us. This is important in the decision-making for these men when these 2 agents are available.
Also at ESMO this year, the data from a small phase 2 randomized trial conducted mostly in Switzerland by SAKK were presented for the first time. That was a maintenance trial post-docetaxel in men benefitting from chemotherapy for metastatic CRPC [castration-resistant prostate cancer], so if those men received docetaxel and responded to that or at least they were not experiencing cancer progression while on chemotherapy. Randomization was between just surveillance post-chemotherapy or maintenance treatment with darolutamide.
The nonsignificant trend favoring darolutamide maintenance was suggested in these men after chemotherapy, which is not a surprise, but it’s good to see. The question is how long should we carry on with the use of these agents even when they have failed? Because all of these men actually had received previous abiraterone or enzalutamide and had failed on these agents. Actually, the longer they had benefit from [abiraterone] or [enzalutamide], the higher the likelihood that darolutamide would work as a maintenance drug post-chemotherapy.
The question now is what should we do with the data, and there is discussion around whether a phase 3 trial should be conducted. Obviously, there are pros and cons, but besides what the final decision will be, it’s more a concept of targeting again and again the androgen receptor in these men, of course either with abiraterone, enzalutamide, or darolutamide, or maybe some new drugs to come. It shows us that the androgen receptor machinery remains active in most men failing abiraterone or enzalutamide, and it may be smart to better target this machinery and to better kill cancer cells.
My experience with darolutamide has been extremely good since the beginning. I was lucky enough to treat the very first patients in the phase 1 trial that we conducted. The first patients responded to darolutamide, second patients responded, and many others. This was true in the phase 1, and the expansion trial confirmed the data. In the phase 1, we couldn’t find adverse effects truly related to the compound. We were wondering whether we had missed something. In larger experience, including phase 3 experience and my own practice with more time, that this drug is exceptionally associated with adverse effects, and most patients don’t complain about adverse effects. It’s easy to handle, and there’s no real need to monitor many things. With all of these drugs, we tend to monitor PSA [prostate specific antigen] and white blood cells, red cells, and creatinine, but this is not related to darolutamide; it’s more about the disease. The drug is easy to handle, and this is beautiful to see.
Darolutamide is indicated and approved in many countries in men with M0 castration-resistant prostate cancer. The next step for this agent is to go to the metastatic castration-sensitive field, and it needs to show a benefit in this setting before it is approved. We are waiting for the ARASENS data combining darolutamide on top of androgen deprivation therapy and docetaxel. The beauty of this trial is that it’s a very large trial. It’s not asking many questions, so it will definitely have the power to address the question, and hopefully we will see the data soon. I’m quite confident knowing what we now know from the PEACE-1 phase 3 trial that darolutamide has a good chance to succeed in this field. It will be important to look at the safety in combination with docetaxel compared to what we already know when enzalutamide or abiraterone are combined with docetaxel in this field.
Transcript edited for clarity.