Dreicer Discusses Emerging Agents in mCRPC

Robert Dreicer, MD

Several investigational agents are on the horizon for patients with metastatic castration-resistant prostate cancer (mCRPC).

“There are new compounds, some of them are first cousins to the current drugs, while others are novel agents,” explains Robert Dreicer, MD. “Newer drugs such, as ODM-201 and ARN-509, are in broad clinical trials in a number of different disease states in prostate cancer. These drugs are being studied in earlier disease states, such as the M0 castrate setting, and in combination with chemotherapy and hormonal therapy in newly diagnosed metastatic disease.”

In an interview with OncLive during the 2017 Interdisciplinary Prostate Cancer Congress, Dreicer, associate director, clinical research, deputy director, University of Virginia Cancer Center, discussed emerging treatments for patients with advanced mCRPC.

OncLive: Please give an overview of the emerging hormonal agents for advanced mCRPC.

Dreicer: Over the last 5 years we have become better informed about abiraterone acetate (Zytiga) and enzalutamide (Xtandi). Clinicians have become more comfortable with these agents. Now, we are increasingly recognizing cross-resistance of these compounds, which is beginning to change how these drugs are prescribed.

There are new compounds, some of them are first cousins to the current drugs, while others are novel agents. Newer drugs, such as ODM-201 and ARN-509, are in broad clinical trials in a number of different disease states in prostate cancer. These drugs are being studied in earlier disease states such as the M0 castrate setting and in combination with chemotherapy and hormonal therapy in newly diagnosed metastatic disease.

There are other new compounds, such as VT-464 and EPI-506, which are somewhat novel agents that are in phase II trials. TAK-385 is for castration sensitive metastatic disease and is an oral GnRH antagonist.

How are abiraterone and enzalutamide currently used?

Due to the recognition of the cross-resistance, clinicians make a judgment to use 1 or the other as their initial therapy for mCRPC. The clinician chooses one of these agents based on what they believe fits the patient profile. Abiraterone requires low-dose prednisone and some patients may have some minor neurological issues.

One may worry about enzalutamide because of its potential CNS toxicities. There are uses for both drugs, but if you get 1 you don’t immediately get the other because there is a lower likelihood of response. Clinicians have become comfortable with both drugs and make decisions based on what they believe is the most appropriate drug for the initial treatment, recognizing that it's not necessarily going to cross immediately over to the other compound.

Can you please discuss the drugs that are currently being studied for earlier stages of disease?

Both ODM-201 and ARN-509 are in large randomized trials of castrate only prostate-specific antigen (PSA) disease. These are drugs that are antagonists similar to enzalutamide and are not currently approved in any stage of prostate cancer. They’re being tested in ongoing, large, international studies in patients with much earlier stages of cancer, where the trial outcomes are timed in metastatic disease. This is a different group of patients that we've not historically used these compounds in.

Should these agents be shown to be beneficial to earlier stages, those results are going to change the paradigm for mCRPC, since patients will have already been exposed to an androgen receptor (AR) antagonist. However, in the meantime, we must wait for the data and determine whether or not these agents provide a positive impact in outcome that would justify treating a group of patients earlier than we typically would.

Please expand on VT-464 and EPI-506.

VT-464 may have some theoretical advantages for patients who have splice variants. Those trials are ongoing so there is not a lot of data to talk about at present. It appears to be a safe agent—it certainly has activity, but the extent of the activity in the clinical setting, which one might ultimately be using, remains unknown.

Overall, what would you like community oncologists to take away regarding novel agents in mCRPC?

It’s important to be aware of the large number of clinical trials that are being conducted with these agents and to encourage participation. It was possible to get enzalutamide and abiraterone FDA approved because of broad participation of oncologists in enrolling patients on trials. We need to continue that momentum in order to understand whether this is the next generation of drugs, either because we’re using them in different disease states or if there are other elements that are beneficial to these patients. We need to obtain results from the studies because we’ve reached a lull in the AR space in terms of new drugs. It's going to take trials to show us where to properly position these compounds.

What are the challenges that are still facing this area?

The main challenge is that we’re not yet curing patients with mCRPC. AR biology remains an attractive target in prostate cancer, but we’ve reached a plateau in terms of the resistance mechanisms. The mechanisms are becoming better defined ways to predict which resistance mechanism might be active in a certain patient, but the data are not yet there. We’re going to need to do more research so we can develop drugs that overcome those resistance pathways.

EPI-506 is a different type of AR antagonist, working at the N-terminal domain. In fact, this is a drug that may have activity in splice variants in AR-V7. However, the data from the phase II trials are not yet mature. We look at EPI-506 as an intriguing possibility that might have different characteristics from the drugs that we use currently.