Karim Fizazi, MD, PhD

: For men with metastatic castration-resistant prostate cancer [mCRPC], things are rapidly evolving, and we now have more weapons to treat these patients. I suspect that very soon, at least in rich countries, many men will receive an AR [androgen receptor] drug early in the course of the disease. Therefore, if a patient develops metastatic CRPC, they will have already exhausted those agents such as abiraterone, enzalutamide, darolutamide, or apalutamide, and we will need other agents to treat patients. Based on the PEACE-1 trial, some of these men also will have exhausted docetaxel chemotherapy.

We will have to decide on other compounds. Obvious options will include cabazitaxel, radium-223, and also PARP inhibitors and lutetium-177 PSMA-617, assuming all of these agents are available and reimbursed in places where patients live. Some other compounds may find their ways to the market. We’re waiting from more data regarding AKT targeting in men with 

 loss. Randomized phase 2 data are very appealing with these agents, and some early phase 3 data are supporting efficacy. We need longer-term data. We’ve seen promising data from early phase 1 with various third-generation androgen receptor antagonists that seem to work in men failing abiraterone or enzalutamide. Hopefully we will soon have phase 3 trial starting to see whether this is true in a larger population of men. For patients with mCRPC, things are changing. More and more we will not use abiraterone, or enzalutamide, or similar agents, because these agents will have been used earlier for better outcomes and for a longer time without disease progression and longer life, as demonstrated in the M1 castration-sensitive disease and in the M0 CRPC setting. We will use different agents, which is excellent for patients because it means that we will show efficacy from these agents in this setting.

In conclusion, for men with metastatic castration-resistant prostate cancer, the last decade has been truly exceptional. We’ve seen a number of agents with tremendous efficacy, including overall survival improvement, and years of overall survival improvement in some spaces. Some of these agents have different mechanisms of action and some of them are not cross-resistant, which means that we can either combine when the safety allows us to do so, or sequence them when we cannot or when the evidence for combining is not there, or not yet there. We have more options to propose to patients, and more are coming. I hope that the next decade will be similar and will provide us as many advantages and as much progress as we saw in the last decade. I’m confident to be honest. Thank you very much.

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An expert discusses the future of metastatic castrate-resistant prostate cancer management.

The Future of Metastatic Castrate-Resistant Prostate Cancer Management

: 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.

Karim Fizazi, MD, PhD, reviews darolutamide data in prostate cancer, including data from phase II clinical trial, ODENZA.

The ODENZA Trial: Metastatic Castrate-Resistant Prostate Cancer

: Enzalutamide, apalutamide, and darolutamide are all approved for use in nonmetastatic castration-resistant prostate cancer, with similar outcomes for efficacy, including overall survival, and seemingly different safety profiles, with no marked difference between darolutamide and its placebo regarding adverse effects. In regard to metastatic castration-sensitive disease, we have data for apalutamide, enzalutamide, and abiraterone; all 3 drugs show overall survival improvement in sometimes different spaces like high risk or low risk, but these 3 drugs work.

We don’t have data with darolutamide in the metastatic castration-sensitive space. We are waiting for the ARASENS large phase 3 trial, which is comparing androgen deprivation therapy plus docetaxel with or without darolutamide. This is eagerly awaited because we recently reported the PEACE-1 data indicating that the triplet treatment with abiraterone improves overall survival. I hope that this is also the case with darolutamide, and data will tell, hopefully soon.

Now, regarding men with metastatic castration-resistant prostate cancer, enzalutamide and abiraterone are approved, while apalutamide and darolutamide are not because we don’t have phase 3 data in this space for these 2 agents.

A key opinion leader discusses impact of ADTs on brain and cognitive function in men with prostate cancer.

Darolutamide in Metastatic Castrate-Resistant Prostate Cancer

: Among what I call the second generation of androgen receptor axis inhibitors, I would clearly list abiraterone, enzalutamide, apalutamide, and darolutamide. Abiraterone is actually an androgen biosynthesis inhibitor, and its metabolism targets the androgen receptor directly. There are 3 drugs directly targeting the androgen receptor: enzalutamide, apalutamide, and darolutamide.

Two of them are chemically very similar; enzalutamide and apalutamide were both invented by the same team and developed by 2 different companies. The chemical structure is very similar and their results from both an efficacy standpoint and a safety standpoint are very similar. For example, we see some fatigue associated probably with the fact that these agents penetrate the blood-brain barrier, some excess in falls and fractures.

The third agent in this family, darolutamide, was invented by a different company in Finland. Its chemical structure makes a curve, which helps the drug not penetrate the blood-brain barrier. Thanks to this property, the drug seems to be better tolerated, at least when we’re comparing each of these drugs with its own placebo in large phase 3 trials. We don’t see much safety difference for darolutamide when compared to its placebo, while we do see some different with the other agents.

We need to remember that many patients with advanced prostate cancer are older than 70, and they might already suffer from cognitive impairment. Of course, this is not always the case, and cognitive impairments can also happen earlier during life. When I started using enzalutamide at full dose in the elderly, many patients complained about having difficulty concentrating or memorizing things, or if it were not the patient, the wife would tell me. Sometimes it was a difficult consultation because the wife was getting either upset or at least scared about what was ongoing, and we realized that in these men, we should probably not use full dose enzalutamide if we want to prevent those adverse effects. When I’m using this agent in the elderly, I tend to use it at half of the dose.

In my experience with darolutamide, we don’t see this happening. This is supported by data from randomized trials when comparing darolutamide with a placebo, we couldn’t see an excess of cognitive impairments or falls and fractures, compared to the placebo.

Dr. Karim Fizazi describes the use of next generation androgen receptor inhibitors in treatment of metastatic castrate-resistant prostate cancer.

Metastatic Castrate-Resistant Prostate Cancer: Androgen Receptor Inhibitors

For most asymptomatic men with metastatic castration-resistant prostate cancer, if they have only received previous androgen deprivation therapy [ADT], which is becoming rarer, the main treatment to be considered is a next-generation hormonal agent, such as abiraterone or enzalutamide. For some of them, basically those with liver metastasis or those very rapidly progressing while on ADT, chemotherapy with docetaxel should probably be an important option to consider. If the patient has exhausted an AR [androgen receptor] drug and if they are asymptomatic, you may consider using chemotherapy with docetaxel, but actually many men are not necessarily willing to go for docetaxel chemotherapy. This is the setting where many ongoing phase 3 trials are taking place because this is truly an unmet need for these men with asymptomatic disease, who don’t want to go for chemotherapy. We need probably more options for these men.

In terms of mechanisms of action and more generally, targets, it’s striking the way that things have been changing in the last 1 to 2 decades. In 2000, we were targeting only the androgen receptor axis with what we had at the time, androgen deprivation therapy, and some weaker drugs, such as bicalutamide, flutamide, and others. Based on the data in 2004, taxane showed efficacy. Sixteen or even more years afterward, we still don’t completely understand how taxanes work and what we are exactly targeting when using a taxane.

Part of the efficacy is probably related to the trafficking in the cells. Part of it might be the trafficking of the androgen receptor, but honestly we don’t know the exact mechanism. In the last years, we saw a new target appearing. Obviously, bone targeting has been there for at least a decade, but now DNA defect repair is a potential target for some patients, and we now have direct evidence that PARP inhibitors work in these patients with DNA repair defects. This is now approved with olaparib and hopefully soon with some other drugs.

In 2021, we showed for the first time that targeting PSMA [prostate-specific membrane antigen], which is a quite specific protein for prostate cancer cells, actually makes a difference, including overall survival improvement for these men, with lutetium-177 PSMA-617. I suspect that soon we will see more ways to target PSMA, using for example, PSMA BiTEs [bispecific T-cell engagers] and hopefully some other ways, maybe ADCs [antibody-drug conjugates]. Starting from AR targeting, we’ve moved to potentially other targets being shown as important, at least for some categories of patients.

The beauty is that AR targeting is probably coming back again. We’ve seen at least 2 generations of AR-targeting agents. The first one would be probably androgen deprivation therapies. Second would be abiraterone, enzalutamide, darolutamide, and apalutamide. I suspect we’re about to see a third-generation drug working when [abiraterone] or [enzalutamide] or similar drugs don’t work anymore, and we saw examples of such drugs from phase 1 experience in recent congresses. This is the future.

An oncologist explains treatment selection and the systemic therapy options available for patients with metastatic castrate-resistant prostate cancer.

Systemic Therapy Options in Metastatic Castrate-Resistant Prostate Cancer

: In the last years, we’ve seen tremendous progress for men with metastatic castration-resistant prostate cancer. If I look at the last decade, we were able to show that using a next-generation hormonal agent was associated with improvement in overall survival in these men, and this was true pre- and post-chemotherapy. The same drugs have been used up front, either in the nonmetastatic castration-resistant prostate cancer space or in the M1 castration-sensitive prostate cancer space, with a greater benefit for the patients.

On top of that, cabazitaxel, a second taxane, was shown to be active even when the first one was not anymore. Bone-targeting agents have shown benefit for patients. This is true for denosumab…in terms of protecting patients from fractures and other skeletal-related events. Radium-223 was also associated with overall survival improvement. More recently, we showed that targeting PSMA [prostate-specific membrane antigen] with lutetium-177 PSMA-617 was also associated with overall survival improvement, even when everything else failed. Also, for a subgroup of men with 

alterations, PARP inhibitors can prolong life. More progress is likely to come.

When a patient develops metastatic castration-resistant prostate cancer, several factors need to be considered before making decisions. One very important one is whether a patient has received ADT [androgen deprivation therapy] alone, which used to be the standard of care years ago, or whether they have received intensification of treatments. Of course, this is now changing the field. We see more patients who have exhausted the first AR [androgen receptor] drugs, such as abiraterone, enzalutamide, darolutamide, or apalutamide when they develop metastatic castration-resistant prostate cancer. Because the cross resistance between these 4 agents is very high, they’re unlikely to work after one of them has already failed.

This is obviously something very important we consider, and in these men, actually taxane chemotherapy is probably the main standard of care. We’ve also demonstrated that for patients who have failed both AR-targeting next-generation hormonal agents plus 1 taxane, we now have at least 2 options with cabazitaxel, a second taxane, and more recently lutetium-177 PSMA-617, which are both associated with improvements in radiographic progression-free survival and overall survival.

We need to dig into details of the biology of the disease, and we now have evidence that choosing a PARP inhibitor, olaparib, in men failing these agents when they have 

 alterations, overall survival is improved. All of those things need to be considered, of course on top of the usual parameters of performance status and patient’s preference.

Karim Fizazi, MD, PhD, provides an overview of advances in treatment of metastatic castrate-resistant prostate cancer.

Karim Fizazi, MD, PhD | Authors

Articles

The Future of Metastatic Castrate-Resistant Prostate Cancer Management

The ODENZA Trial: Metastatic Castrate-Resistant Prostate Cancer

Darolutamide in Metastatic Castrate-Resistant Prostate Cancer

Metastatic Castrate-Resistant Prostate Cancer: Androgen Receptor Inhibitors

Systemic Therapy Options in Metastatic Castrate-Resistant Prostate Cancer

An Overview of Metastatic Castrate-Resistant Prostate Cancer